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Antigen Recognition by γδ T-Cells

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Introduction

Activated T lymphocytes are an integral part of atherosclerotic plaques, and recent observations suggest that they play a role in the inflammatory response in atherogenesis (Gown et al 1986; Jonasson et al 1986; Emeson and Robertson, 1988; van der Wal et al 1989; Hansson and Holm, 1989; Ross 1993). Both αβ and γδ T-cells have been identified among the CD3+ T-cells, which make up the T-cell component of the infiltrate in atherosclerotic plaques. Although sparse in numbers among the inflammatory infiltrate in atherosclerotic arteries, the γδ T-cell is, nevertheless, enriched in injured arteries and early atherosclerotic lesions, and may play a role in the early stages of atherogenesis (Kleindienst et al 1993; Xu et al, 1993; Heng et al, 1994). This Chapter summarizes current knowledge concerning the immune function of this interesting and potentially important lineage of T-lymphocytes, focusing on structure of the TCR γ and δ chains, the antigens recognized by γδ T-cells, as well as mechanisms of antigen recognition. Since γδ T-cells are enriched in atherosclerotic arteries, and antigen-T-cell receptor interactions initiate T cell-mediated immune responses, consideration of cognate γδ T-cell antigens may be the means of identifying potential triggers of atherogenesis.

T-cell antigen receptor (TCR)-dependent T cell stimulation is mediated by engagement of the antigenic ligand to the TCR (Davis and Bjorkman 1988; Caccia and Mak 1989; Davis 1990). The TCR is composed of clonally variable αβ or γδ heterodimers, covalently associated with invariant components of the CD3 polypeptides (Bluestone et al 1987; Allison and Lanier, 1987; Raulet 1989; Allison and Raulet, 1990). In T-cells of the αβ lineage, recognition of both the foreign antigenic peptide and the major histocompatibility complex (MHC) molecule is achieved by a single heterodimeric antigen-receptor structure (Allison and Lanier, 1987; Marrack and Kappler, 1986), with the antigen recognition component composed of clonally variable disulfide-linked α and β chains (Garmain et al 1986; Saito et al, 1987). While much is known about the function, mechanisms of antigen recognition and antigenic repertoire of αβ T-cells, these aspects remain largely enigmatic in γδ T-cells. Nevertheless, we find it useful to compare and contrast what is currently known concerning the antigenic repertoire and basic mechanisms of antigen recognition in both lineages, in order to further define the functional role of both αβ and γδ T-cells in atherogenesis. In this Chapter, we will focus particularly on various relevant aspects of antigen recognition particularly pertaining to γδ T-cells.

Ontogeny and Chromosomal Location of TCRγδ Gene Segments

The γδ T-cell is, ontogenetically, the more primitive of the two lineages, and appears earlier in T-cell differentiation than the αβ counterpart. Two distinct T cell receptors are observed during thymocyte development, with T-cells expressing the TCRγδ being the first to appear (Pardoll et al 1987; Havran and Allison, 1988). These are observed by day 14 in the thymus, by day 21 in the spleen and epidermis. By day 18, the γδ T-cells predominate in the thymus, decreasing to 1% at birth due to an increase in αβ T-cells (Pardoll et al 1988).

The T-cell antigen receptor (TCR) complex is intimately involved in antigen recognition. With respect to the γδ T-cell, the TCR γ chain genes are located on chromosome 13 in the murine species (Krantz et al 1985). In humans, they map to the short arm of chromosome 7 (Rabbitts et al, 1985; Murre et al 1985). In both murine and human genome, the TCR δ chain genes map to chromosome 14, situated between the Va and Ja gene segments (Chien Y et al 1987; Greisser et al 1988).

Structure of the TCRγδ Gene Segments

The TCR gene loci encoding the γ and δ heterodimeric chains consist of V (variable) and J (joining) gene segments, or V (variable), D (diversity), J (joining) and C (constant) gene segments, which undergo rearrangement to generate functional genes. Excellent reviews on this subject are available (Raulet 1989; Kronenberg et al 1986; Allison and Havran, 1991). The γ locus consists of four Jγ genes, each associated with a Cγ gene and 7 Vγ genes (Hayday et al, 1985; Garmain et al 1986; Iwamoto et al; Pelkonen 1987), with the Vγ genes rearranging to the Jγ segments in 3 functional sets: Vγ5, Vγ2, Vγ4 and Vγ3 with Jγ1/Cγ1; Vγ1.2 with Jγ2/Cγ2; and Vγ1.1 with Jγ4/Cγ4 (Raulet 1989; Allison and Havran 1991). The δ locus is located within the a locus between the Vα and Jα segments (Chien et al 1987). About 10 Vδ genes that rearrange to Dδ/Jδ-Cδ segments have been identified (Chien 1987; Korman et al ; McConnell et al 1989). A comparison of the genomic organization of the TCRγδ gene families is shown in figure 1.

Figure 1. This figure shows the genomic organization of mouse and human TCRγδ gene families.

Figure 1

This figure shows the genomic organization of mouse and human TCRγδ gene families. The exons of the C genes are not depicted. The data is adapted from Raulet DH. Annu Rev Immunol 1989;7:175-207, and Allison & Havran (Annu Rev Immunol (more...)

Rearrangements of the different segments in the germline or variable gene segments reflect the diversity in antigenic repertoire. The junctional diversity, on the other hand is achieved by the utilization of more than one diversity (D) segment, and by the insertion of one or more N (nongermline) segments. This may occur from differential trimming of the termini of the recombining gene segments by an exonuclease, or by insertion of template-independent nucleotides by terminal transferase (Tonegawa et al 1983). It has been pointed out that while the TCR γ and δ loci contain fewer V and J segments than the α and β locus, extensive junctional diversity is observed in the rearranged γ and δ genes (Elliott et al 1988). It is pointed out that diversity of the TCR δ chain appears to be more extensive in adult tissue than in fetal tissue (Allison and Havran 1991; Elliott et al 1988; Mosley et al 1994), suggesting perhaps the exposure of adult animals to antigens not yet exposed to in fetal tissue.

Antigen Recognition and Antigenic Repertoire of γδ T-Cells

In αβ T-cells, the mechanism of T-cell stimulation differs depending on the nature of two distinct classes of antigenic ligands. The antigens which stimulate the TCRαβ are classified as conventional antigens or superantigens, depending on certain immune requirements or preconditions. Activation of αβ T-cells by conventional antigens require prior antigenic challenge. On the other hand, prior antigenic priming appears not to be necessary for superantigen-triggered T-cell responses (Herman et al 1991).

In the case of conventional antigens, the αβ T-cell recognizes these antigens as peptide fragments in the context of class I or class II major histocompatibility complex (MHC) molecules. This process involves prior intracellular processing of the antigen by antigen presenting cells (APC), followed by the binding of the processed peptide ligand to various sites on the antigen-presenting groove on the major histocompatibility complex (MHC) molecule of the APC and eventual presentation at the cell surface to the TCR (Bjorkman et al 1987; Bluestone et al, 1992; Jorgenson et al 1992; Rudensky et al, 1991; Kropshofer et al 1992). This process results in T-cell activation and clonal proliferation of T-cells. These T-cell clones generated in response to specific antigens are identified by their characteristic utilization of certain TCR junctional sequences. Superantigens, on the other hand, do not require intracellular processing for antigen recognition. The bacterial superantigens are native proteins, 20-30 kDA in molecular weight (Herman et al 1991). These proteins bind to sites on the MHC and TCR other than those engaged by conventional peptide antigens, generating polyclonal T-cell responses characterized by the utilization of TCR Vb genes rather than junctional sequences (Herman et al 1991).

Antigenic Repertoire of γδ T-Cells

Current evidence suggests that conventional and superantigens which stimulate αβ T-cells do not, as a rule, stimulate γδ T-cells, suggesting that γδ T-cells recognize and are specifically stimulated by a different repertoire of antigens. With respect to the repertoire of antigens recognized by γδ T-cells, observations are available in both human and experimental animal studies. Subsets of γδ T-cells have been found to increase during certain infectious diseases in humans. Increases in the population of γδ T-cells have been reported in viral infections such as Epstein-Barr (De Paoli et al, 1990), HIV-1 infections (De Paoli et al 1991), and a variety of bacterial infections, including tuberculosis (Barnes et al, 1992). T lymphocytes bearing the TCRγ/δ feature prominently in experimental infections induced in mice by Listeria monocytogenes and an avirulent strain of Salmonella (Hiromatsu et al, 1992; Emoto et al, 1992). The above observations suggest that the antigens recognized by γδ T-cells during such infections may either be components of the infectious agents themselves, or molecules produced by the infectious organisms as a result of the “stress” of host-parasite interaction.

There is accumulating evidence that γδ T-cells are stimulated by certain stress or heat-shock proteins (Hsp) generated by a variety of cells during stress. These stresses include interactions between host and tumor cells (Fisch et al, 1990), and against various bacteria (Shinnick et al, 1988; O'Brien et al, 1989; Pfeffer et al, 1990). Heat shock proteins are among the most conserved proteins in all of biology, with a high degree of homology between hsp produced by species as diverse as bacteria and man. The γδ T-cell is shown to react with focused specificity to the 65 kDa Hsp produced by Mycobacterium tuberculosis, and its mammalian homolog, the 60 kDa Hsp (Shinnick et al, 1988; O'Brien et al 1992). The fact that γδ reactivity correlates with the utilization of certain V genes after antigenic challenge (Fisch et al, 1990; Pfeffer et al, 1992), suggests that γδ reactivity is triggered by specific TCR-mediated ligand recognition. It is inferred from the usage of certain TCR Vγ genes that each clone responds to the same or similar ligands rather than to a variety of structurally different ones (Fu et al, 1994). Unlike αβ T-cells which possess a large number of Vβ genes capable of rearranging to respond to a wide variety of antigenic ligands, the Vβ gene repertoire of γδ T-cells appear to be limited (Happ et al, 1989; Havran et al 1989; De Libero et al, 1991). In fact, the entire subset of γδ T-cells is observed to respond to a single epitope on Hsp60 (O'Brien et al 1991). In one study using T-cell hybridomas, the majority of γδ T-cell hybridomas with TCR gene rearrangements expressing Vγ1-Jδ4-Cδ4 and Vδ6-Cδ chains showed constitutive activation to secrete IL-2 in response to mycobacterial products (purified protein derivative or PPD) and mycobacterial Hsp60 (O'Brien et al, 1989; Born et al, 1990).

It has also been observed that unlike γδ T-cells obtained from the lymph nodes, thymus, or epidermis which show limited diversity of γδ TCR genes (Arsanow et al, 1988), γδ T-cells from intestinal epithelium show rearrangements of 3 of 6 V region γ genes (Vγ1, Vγ2, and Vγ5), with rearrangements of 5 of 7 Vδ genes (Vδ2, Vδ3, Vδ4, Vδ5 and Vδ6), with substantially more diversity in the V-J and V-D-J junctional regions (Moseley et al, 1994). One explanation for the diversity of Vγ and d gene rearrangements in γδ T-cells from intestinal epithelium may lie in the fact that, unlike the spleen, lymph nodes and blood, the intestinal tract is continually exposed to environmental stimuli such as luminal bacterial and fungal antigens (Mosley et al, 1994). In support of this notion are studies showing alteration of phenotypic composition and immunologic responses of murine intestinal epithelial γδ cells induced by differences in intestinal microflora (Lefrancois and Goodman 1989; Bandeira et al 1990).

Mechanisms Involved in Antigen Recognition byγδ T-Cells

Although it is widely accepted that T-cells that express the αβ TCR recognize foreign antigens as processed short chain linear peptides presented by the MHC molecules to the TCR at the cell surface (Bjorkman et al, 1987; Germain, 1986), the mechanisms involved in antigen recognition by γδ T-cells are less clear. Although current evidence indicates that the antigenic repertoire of γδ T-cells differs from that of αβ T-cells, there are certain antigens that are capable of stimulating both populations. For example, staphylococcal enterotoxin A, a superantigen capable of activating αβ T-cells, appear to be also recognized specifically by γδ T-cells, as evidenced by monoclonal expansion of T-cells expressing the Vγ9 region (Rust et al, 1990). Nevertheless, despite these apparent exceptions, evidence indicates that the antigenic repertoire of γδ T-cells differs from those of their TCRαβ-bearing counterparts, suggesting the possibility of different mechanisms in antigen recognition employed by γδ T-cells.

Non-Requirement for Classical MHC in Antigen Recognition by Some γδ T-Cells

It has been known for many years that peptide fragments from influenza nucleoprotein are capable of stimulating cytotoxic T-cells, and that the epitopes of this foreign antigenic protein recognized by these TCRαβ-bearing lymphocytes are short chain peptides (Townsend et al, 1985; Townsend et al, 1986; Taylor et al, 1987). It has also been shown that MHC class I molecules are involved in recognition of viral antigens by cytotoxic T lymphocytes, and that binding of the processed foreign peptide to the MHC class I molecule is involved in T-cell recognition of the viral antigen (Schultz et al, 1991). MHC class I antigens, which function as peptide receptors, subsequently present peptides derived from cellular proteins at the cell surface for surveillance by αβ T-cells (Rammesee et al, 1993). Under normal circumstances, all the peptides presented are derived from normal cellular proteins, to which the T-cell is tolerant. If the cell is infected by a virus, foreign peptides are presented in addition to self peptides. These foreign peptides are recognized by the αβ T-cells, resulting in the triggering of a cytotoxic immunological response directed towards the infected cell (Wabuke-Bunoti et al, 1984; Townsend et al, 1985; Townsend et al, 1986).

MHC class I molecules are glycoproteins consisting of a heavy chain and a light chain or β2-microglobulin. The heavy chain is made up of three a extracellular domains, α1-3, a transmembrane portion and a cytoplasmic tail. The heavy chains of MHC class I molecules are encoded on chromosome 6 in humans and on chromosome 17 of the mouse. β2-microglobulin is covalently attached to the β3 domain. The peptide antigen binding site, revealed by X-ray analysis of HLA-A2, Aw68 and B27 crystals, consists of a groove formed by the α1 and α2 domains and a β-pleated sheet (Bjorkman et al, 1987; Saper et al, 1991). The antigen binding groove, 1X1.2 nm in dimension, accommodates a short peptide chain of 8-10 amino acids. It has been shown that the MHC class I antigen binding groove may accommodate amino acids derived from foreign proteins, such as viral peptides (Zimmermann et al, 1992). This issue is addressed in Chapters 1 and 9.

In addition, it is suggested that the structure of the antigen-binding groove of the MHC class I molecule determines the selection of self peptides (van Bleek and Nathenson 1991). It appears that self-peptides occupy specific pockets associated with the antigen-binding groove on the MHC class I molecules (Garrett et al, 1989). One explanation is that the TCR may recognize both the foreign antigen and the self-peptides as a single complex (see fig.2. It is also suggested that MHC class I molecules function in the presentation of samples of self-peptides at the cell surface for surveillance by T cells (Rammensee et al, 1993). In support of this hypothesis are studies showing that tolerance to self-antigens is MHC class I molecule-restricted (Rammensee et al, 1984; Falk et al, 1992).

Figure 2. Recognition of foreign antigen and self-peptide by α/β T-cell antigen receptor as single complex.

Figure 2

Recognition of foreign antigen and self-peptide by α/β T-cell antigen receptor as single complex.

Although there is ample evidence that γδ T-cells recognize self-antigens, it is, however, unclear whether γδ T-cells recognize all antigens in the context of the MHC molecule. While O'Brien et al observed that the majority of the γδ T-cell hybridomas did not require MHC for stimulatory activity, at least one clone was stimulated by antigen in a MHC-restricted manner (O'Brien et al, 1989). In addition, there is evidence that γδ T-cells may recognize some antigens in a MHC-restricted manner. Such is the case with tetanus toxoid, which appear to require MHC for antigen presentation to TCRγδ (Kozbor et al, 1989). On the other hand, Bluestone's group has identified a murine TCRγδ clone (TgI4.4) that recognizes a herpes simplex virus type 1 (HSV-1) transmembrane glycoprotein, gI, in an MHC class I- and class II-independent manner (Johnson et al 1992). In this study, reactivity by Tg14.4 to gI was assayed by the production of IFN-γ and lysis of HSV1-infected cells. These investigators found that TG14.4 lysed HSV-1-infected fibroblasts from different haplotypes and from class I MHC-deficient β2 microglobulin mutant mouse. Of interest is the observation that the TCRγδ+ MHC-restricted clone responding to tetanus toxoid was CD8+, thus differing from the CD8- Tg14.4 MHC-unrestricted clone responding to HSV-1 glycoprotein I.

γδ T-Cells May Recognize Unprocessed Protein at the Cell Surface

Not only have investigators found that the majority of γδ T-cells appear to recognize antigens without involvement of classic MHC molecules, some clones of γδ T-cells were observed to be capable of recognizing unprocessed proteins, including mouse class II MHC molecule IEk, the nonclassical MHC class I molecules T10 and T22, and herpes simplex virus glycoprotein I, respectively. Surprisingly, these clones were found to be unable to either recognize peptides bound to these proteins, or peptides derived from these proteins (Chien 1996; Schild et al, 1994; Schild et al, 1994; Weintraub et al, 1994; Sciammas et al, 1994). In these studies, γδ T-cells appear to recognize protein and nonprotein antigens directly on the surface, without the need of intracellular antigen processing.

The requirement for cell-surface expression of the antigen by γδ T-cells is shown in studies using stimulation of the γδ Tcell clone (Tg14.4) by HSV-1 glycoprotein I (Sciammas et al, 1994). In these studies, the lack of surface expression of glycoprotein I resulted in lack of stimulatory response by the γδ T-cell clone, suggesting the requirement for the cell-surface expression of the antigen. Similarly, Schild et al (Schild et al 1994) used surface expression of T10/Ld, a chimera of the a1 and a2 domains of T10 and a3 domains of an MHC class I Ld molecule to stimulate responses in G8 clone of γδ T-cells. He observed that stimulation of G8 correlated directly with the degree of surface expression of the T10 ligand, again indicating the requirement for cell-surface expression of the antigen in antigen-recognition. Additionally, in DBA/2 mice immunized with the synthetic copolymer, GT (Glu-Tyr), Vidovic (Vidovic et al, 1989) studied a γδ T-cell hybridoma, which responded to GT only in the presence of stimulator cells expressing the Qa-1b but not the Qa-1a molecule. He found that this response was blocked by anti-Qa-1b antibody, which bound to the cell-surface expressed Qa-1a molecule, presumably by interfering with the antigen-Qa-1a complex recognition by the γδ T-cell antigen receptor at the cell-surface level. The above body of evidence suggests that γδ T-cell recognition may involve binding of antigen by TCRγ/δ at the cell surface (Chien 1996).

Intracellular Processing Is Not Required for Antigen-Recognition by Some γδ T-Cells

The requirement for intracellular processing in antigen-recognition by γδ T-cells has been assessed by Schild et al, 1994. Taking advantage of the fact that experiments performed at 39°C interfered with endosomal acidification and intracellular processing of antigens, Schild et al (1994) observed temperature independence of IL-2 production by the LBK5 γδ T-cell clone responding to IEk expressed on temperature sensitive CHO cell mutants. The results of these experiments indicate the lack of requirement for intracellular processing of the IEk antigen by the LBK5 clone, which in turn supports the concept that intracellular processing of antigens is not required for recognition by some γδ T-cell clones. In contrast, the IL-2 response of the 2B4 αβ T-cell clone to IEk was observed to be blocked by elevation of the temperature from 34°C to 38°C, supporting the requirement for intracellular antigenic processing in the αβ T-cell clones. Similarly, experiments using the G8 γδ Tcell clone, which recognizes the product of the nonclassical class I T10 and homologous T22 gene (94% homology), again demonstrate that the conventional antigen-processing pathways are not required for antigen recognition by some γδ T-cells (Weintraub et al, 1994). In another experiment, the T22 molecule, a ligand of clone KN6, is shown to stimulate KN6 in T22-expressing cells deficient in the class I peptide transporter, again indicating that intracellular processing may not be required in antigen recognition by γδ T-cells (Bonneville et al, 1989). Similarly, convincing evidence which support the nonrequirement for intracellular antigen-processing by γδ T-cells is provided by the demonstration of TCRγ/δ recognition of gI, a transfected herpes simplex type 1 transmembrane glycoprotein expressed on the cell surface of Tg14.4 and RMA-S γδ T-cell clones. RMA-S cells are mutant cells incapable of processing antigens intracellularly (Sciammas et al, 1994) because they lack the TAP-1 gene, which encodes a component involved in transport of processed peptides to the endoplasmic reticulum. The observation that both Tg14.4 and RMA-S cells lysed glycoprotein I+ transfected cells with equal efficiency suggests that intracellular antigen processing is not required for TCRγδ recognition of HSV-1 glycoprotein I. Evidence in support of surface recognition of Hsp60 by γδ T-cells is provided by Fisch et al who immunoprecipitated Hsp60, identified by iodinated rabbit anti-Hsp60 polyclonal antibodies, on the surface of Daudi cells (Fisch et al, 1990). Additional evidence is provided by similar studies by Jarjour, who also demonstrated the expression of Hsp60 on the surface of γδ T-cells (Jarjour et al, 1990).

Thus unlike αβ T-cells, which recognize processed conventional antigens modified by the intracellular pathway, and presented in the context of MHC molecules (Buus et al, 1986; Rotzschke and Falk, 1991; Attaya et al, 1992; Spies et al 1992), the requirements for antigen recognition by γδ T-cells appear to differ considerably. The nonrequirement for intracellular antigen processing, however, is not unique to γδ T-cells, as superantigens are processed extracellularly prior to binding to MHC class I molecules and to αβ T lymphocytes (Sherman et al, 1992).

Are Antigen-Presenting Cells Necessary For Antigen-Recognition by γδ T-Cells

The function of the antigen-presenting cell lies in the intracellular processing of protein molecules to produce linear peptides which are presented at the cell surface in the context of the MHC molecules for recognition by the TCR. There is evidence, however, that class Irestricted presentation may occur without internalization or processing of exogenous antigenic peptides (Hosken et al, 1989). The ability of the γδ T-cells to recognize unprocessed protein antigens at the cell surface without the requirement for intracellular processing suggests that for many antigens, antigen-presenting cells may not be an absolute requirement for antigen-recognition by γδ T-cells. However, even in these cases, antigen-presenting cells may still be involved in immune processes mediated by γδ T-cells, as suggested by observations of multiple interactions between γδ T-cells and macrophages (fig. 3). It is possible in such cases, that the macrophages may not function in antigen recognition. Lymphokines produced by activated γδ T-cells may prime macrophages to respond to other stimuli, including lipopolysaccharides. Activated macrophages, stimulated in this way produce large amounts of cytokines and growth factors, thus adding greatly to the cytokine load in the inflamed tissues. The cytokines and growth factors activate both immune and nonimmune target cells, thus enhancing the immunological response.

Figure 3. Ultrastructure of Injured Human Artery showing direct contact (arrowhead) between a dendritic γδ T-cell (DT) and macrophage (M) -γδ T-cell-macrophage interaction.

Figure 3

Ultrastructure of Injured Human Artery showing direct contact (arrowhead) between a dendritic γδ T-cell (DT) and macrophage (M) -γδ T-cell-macrophage interaction. The dendritic γδ T-cell is characterized (more...)

Structural Requirements of Antigens Recognized by γδ T-Cells

Current data support the belief that configuration of the antigen, which affects surface cross-linking to the γδ T-cell receptor, affects recognition by γδ T-cells. This is based on studies which show that amino acid substitutions in the floor of the antigen-binding site affect recognition by the γδ T-cell receptor (Esquerra et al, 1992; Chien 1996). Thus, it appears that TCRγδ may resemble immunoglobulins in the way these cells recognize antigens, further supporting the notion that γδ T-cells and αβ T-cells recognize antigens differently (Chien, 1996).

To define the structural requirements for antigenic peptides for recognition by γδ T-cells, Fu et al used synthetic peptides derived from mycobacterial Hsp60 to stimulate murine Vγ1+ hybridomas transfected with γδ TCR genes to secrete lymphokines (Fu et al, 1994). These investigators found that the smallest Hsp60 peptide capable of stimulating the γδ T-cell hybridomas is 7 amino-acids long, having the sequence FGLQLEL, and corresponding to positions 181-187. A longer peptide with essentially the same core (p180-190) altered by amino acid substitutions, revealed certain amino acids necessary for stimulatory activity of γδ T-cells. Substitutions of phenylalanine in position 181 and leucine in position 183 abolished responses in all Hsp60 reactive γδ T-cells. Amino acid side chains at position 185 and 187 appear also to be important for the activation of some clones. However, it was pointed out that the mycobacterial Hsp60 sequence covered by p181-187 is not the optimal amino acid sequence for stimulation of γδ T-cells (Fu et al, 1994), suggesting perhaps that a larger molecule may be required for optimal antigenic stimulation.

The specificity of antigenic stimulation of the γδ T-cell receptor may be shown by stimulation of specific γδ T-cell Vγ clones by different antigens. Thus, Jurkat cells transfected with human Vγ9 gene, and either Vδ1 or Vδ2, have been shown to respond specifically to staphylococcal enterotoxin A (Loh et al, 1994). The antigenic repertoire of γδ T-cells appear to be rather heterogeneous. Thus, peptides corresponding to a hydrophobic segment of mycobacterial hsp60 are shown to stimulate a Vγ1 clone of γδ T-cells (Fu et al, 1994). Inorganic side chains and other nonpeptide molecules may also be antigenic, as shown by observations that a phosphate-containing molecule from mycobacterial extract is able to stimulate Vγ9Vδ2 bearing T-cells (Schoel et al, 1994). In addition, γδ T-cells are stimulated by nonpeptide antigens to produce a clone expressing Vγ2/Vδ2 rearranged genes (Bukowski et al, 1995). The Vγ9 bearing γδ T-cells are also activated to respond by clonal expansion to Salmonella infection (Hara et al, 1992). Thus, the antigenic repertoire of γδ T-cells may include whole protein, peptide and even nonpeptide antigens. However, it is uncertain, in the case of inorganic molecules, whether the phosphate and other inorganic molecules directly engage the antigen receptor or nonspecifically lower the threshold for stimulation by the low molecular weight mycobacterial ligand (Schoel et al, 1994).

Antigen-Recognition and TCRγ/δ Variable Gene Usage

Studies have been done showing a correlation between TCR-γδ variable gene utilization and recognition of a given antigen (Happ et al, 1989; Sturm et al, 1991). The recognition of HSV-1 transmembrane glycoprotein I by Tg14.4, a γδ T-cell clone isolated from murine lymph nodes, has been shown to stimulate the Vγ1.2,Vδ8 chain utilization (Sciammas et al, 1994). A minor population of γδ T-cells has been shown to utilize Vγ1/Vδ6 TCR genes in response to the heat shock protein, Hsp60 (Reardon et al, 1994). T-cells expressing the Vγ1/Vδ6-TCR genes were originally identified in the thymus (Happ et al, 1989), but has since been found in many extrathymic organs and tissues, including the spleen and lymph nodes (O'Brien et al, 1992), epidermis (Esquarra et al, 1992; Ota et al 1992), liver (Roark et al, 1993), gastrointestinal and reproductive systems (Nagler-Anderson et al, 1992; Heyborne et al, 1992). The extrathymic origin of γδ T-cells is emphasized by the discovery of this lineage in athymic mice (Payer et al, 1992).

Gene transfer studies demonstrate that the Vγ1/Vδ6-TCR is essential for autoreactivity (Kikuchi et al, 1992). A Vγ1/Vδ6-TCR+ hybridoma (70BET-2.12) derived from a minor γδ T-cell population from murine epidermis has been shown to respond to whole Hsp60 as well as to a 17mer Hsp60 derived peptide from M. lepra, with a ten-fold production of IL-2 above spontaneous levels (Reardon et al, 1994). Although the 70BET-2.12 hybridoma resembled other Vγ1/Vδ6-TCR cells in their ability to spontaneously produce cytokines, presumably due to autoreactivity, they differed from the cell lines of Ezquarra et al (Esquarra et al, 1992) in their reactivity to whole Hsp60 protein and hsp60 peptides. Comparison of the amino acid sequences of Vγ1/Vδ6-TCR of 70BET-2.12 of Reardon et al (Reardon et al, 1994) with those of the Vγ1/Vδ6-TCR cells of the epidermal cell lines (Y93A, Y245, T195) and thymic hybridoma (CC48) of Esquarra et al (1992) showed a high degree of similarity between the Vγ1 and Vδ6 and J (junctional) TCR sequences, but considerable dissimilarity between the N (nongerm line) and D (diversity) regions of the TCR. The findings from these investigators are shown below in Figure. 4.

Figure 4. This figure shows the TCR variable (V), junctional (J), and nongerm-line (N) sequences in γδ cell lines and hybridomas from epidermal and thymic sources (Reardon et al, 1994; Esquarra et al, 1992).

Figure 4

This figure shows the TCR variable (V), junctional (J), and nongerm-line (N) sequences in γδ cell lines and hybridomas from epidermal and thymic sources (Reardon et al, 1994; Esquarra et al, 1992).

From an examination of TCR sequences in the various γδ TCR+ clones, it is clear that the variation is minimal among the Vγ1 and Vδ6 variable gene sequences from the epidermal and the thymic γδ T-cell clones studied by Reardon (Reardon et al, 1994) and Esquarra et al (1992). With respect to the junctional gene sequences, the variation is also minimal among the Jγ4 gene sequences, and somewhat greater among the Jδ1 sequences. However, the greatest dissimilarity was observed between the N (nongerm line) and the D (diversity) sequences of the TCRδ chain. It has been suggested that the extensive dissimilarity in the diversity sequences suggests that the potential repertoire is as large or even larger than that of αβ T-cells (Davis 1988; Allison and Havran, 1991).

However, there may be an alternative explanation for the extensive dissimilarity in the N and D sequences of γδ T-cells. It is pointed out that the extraordinarily large number of amino acids in the N1-Dd1-N2-Dd2-N3 region of the TCRδ chain suggests the ability to accommodate large antigenic molecules, i.e., proteins, directly on the cell surface without the requirement of prior intracellular processing. Since the antigenic epitopes are recognized by the V and J portions of the TCR, we hypothesize that the utilization of dissimilar N and D portions of the TCRγδ molecule observed in the clones of Reardon and Esquarra may reflect the ability of the TCRγδ to respond to hsp60 of different sizes. The Hsp60-reactive γδ T-cells cells in liver and spleen show differences in TCR junctions, suggesting that different sizes of Hsp60 epitopes are recognized by these cells (Roark et al, 1993). In our laboratory, in specimens from a number of hypoxic human mesenteric artery branches processed for electron microscopy, we observed the presence of tannic acid stained Hsp60 of different sizes directly juxtaposed to the surface cell membranes of dendritic γδ T lymphocytes (Heng et al 1994). These may reflect different sizes of polymerized Hsp60 proteins in the tissues (Fig. 4).

Role ofγδ T-Cells in Immune Defense

The functional role of γδ T-cells in health and disease is still under debate. Although there is evidence that γδ T-cells are able to recognize a heterogeneous array of ligands, the relatively small number of germ-line elements available for the construction of functional TCR genes also support the concept of a limited γδ T-cell repertoire. In several murine species, γδ T-cells comprise the major T-cell component in epithelial tissues. Allison and Havran point out that the γδ TCR of these epithelial γδ T-cells have essentially no diversity, and postulate that these cells may play a role in immunological surveillance for self-induced antigens rather than foreign antigens (Allison and Havran, 1991). Several investigators independently report that Vγ1/Vδ6-TCR+ cells show spontaneous cytokine production (Reardon 1994), i.e., in the absence of a recognizable external stimulus. This suggests that this subset may represent lymphocytes activated by self-peptides.

Studies using mice lacking either αβ or γδ TCR show that γδ T-cells also participate in immunological responses, but in a way which is distinct from the αβ TCR-bearing subset (Mombaerts et al, 1993; Viney et al, 1994). These experimental studies involve either the use of mutant mice devoid of T-cells expressing either αβ or γδ TCR, or exploit deficient TCR function by the use of specific monoclonal antibodies against either TCRα/β or TCRγ/δ. Current evidence shows that both lineages are important in immune protection against infectious organisms. Deficiencies in both αβ and γδ T-cells result in greater severity of disease in cells infected with Mycobacterium sp. (Kaufmann 1994), Leishmania sp. (Rosat et al, 1993), and Plasmodium sp. (Tsuji et al 1994), while the presence of γδ T-cells appear to allow some protection against infection in αβ deficient mice (Hiromatsu et al, 1992; Kaufmann 1994). Differences between immune responses have been observed, with γδ T-cells clearing bacteria in the early stages of infection (Hiromatsu et al, 1992), and αβ T-cells clearing bacteria in the later stages (Hiromatsu et al 1992); Kaufmann et al 1994). However, this early response is not seen in viral infections (Carding et al, 1990). There is some evidence that the γδ T-cells are capable of responding differently to different pathogens, with production of different cytokines in response to different antigens. It has been observed that γδ T-cell clones show differential production of interferon-γ and IL-4 production respectively in response to Th1 and Th2-stimulating pathogens (Ferrick et al, 1995). However, the immune response in these deficient mice may not be strictly analogous to that in humans. First, since the immune response is enhanced by the simultaneous presence of both TCRγδ+ and TCRαβ+ subsets, the deletion of one of these subsets would be expected to result in diminished immune responses to an antigenic stimulus. Furthermore, the immune responses achieved in experimental animals with no comorbid disease may not be comparable to that in atherosclerotic humans with two or more comorbid risk factors, in view of the immune enhancement produced by the synergistic interaction of two or more stimuli (Chapter 9).

Role of Heat Shock Proteins in the Physiological Response to Stress

The stress response is ubiquitous for all eukaryocytes. In the presence of adverse physiologic or environmental conditions, the organism is induced to synthesize a highly conserved family of proteins, also known as stress-induced or heat shock proteins (hsp). These include Hsp20 or α-crystallin-related proteins (Morimoto 1991), and other small heat shock proteins, which respond to high temperature stress (Wehmeyer et al, 1996); Hsp70, which facilitates protein folding and translocation to endoplasmic reticulum and mitochondria (Chirico et al, 1988; Kang et al, 1990); GRP78, which is synthesized constitutively but also inducible by glucose deprivation; Hsp75, which is involved in ATP-dependent translocation across the outer mitochondrial membranes; and Hsp90, a component of steroid receptor complexes (Morimoto 1991). An additional stress protein, Hsp60, has been shown to stimulate TCRγ/δ-bearing lymphocytes. Although Hsp60 has also been thought to be involved in protein folding in mitochondria (Ostermann et al, 1989), Hsp60 is now considered the dominant self-antigen candidate for the selection of γδ T-cells (Bell 1995).

In a recent review, Morimoto (1991) pointed out that transcription of Hsp70 genes can be inducible by heat shock, amino acid analogues, heavy metals, inhibitors of energy metabolism, fever, hypertrophy, oxidant injury, ischemia, antineoplastic chemicals and viral infections. However, although some heat shock proteins, such as Hsp70, are constitutively produced, and can be stimulated by nonstressful conditions, such as cell cycling, cell development and differentiation, they tend to do so particularly when these processes are stimulated by growth factors (Morimoto 1991). The heat shock response has been considered a process whereby, as a result of physiological stress, a discrete set of proteins, known as heat shock proteins are preferentially synthesized. These proteins are essential for stimulation of a series of protein biosynthetic events, including protein folding, oligomerization, translocation and secretion. It has been proposed that under conditions of physiological stress, heat shock proteins act as intracellular sentinels to recognize malfolded proteins. The stress response has been considered as a means for activation of transient inducible transcriptional events in response to cell damage, cell transformation and abnormal cell differentiation (Morimoto 1991). In healthy organisms, the synthesis of heat shock proteins tends to be protective as shown by numerous myocardial stunning studies. This is due to the fact that a single stimulus tends to induce a negative feed back or homeostatic response. However, in the presence of comorbid disease or multiple stimuli, the presence of hsp60, which is the cognate antigen recognized by γδ T-cells, tends to induce synergistic or disregulated immune responses which may enhance existingatherosclerosis. The immunogenicity of Hs60 is further discussed below.

Immunogenicity of Hsp60 During Autoimmune and Bacterial Inflammation

From an evolutionary view point, heat shock proteins are highly conserved stress proteins, with conserved sequence homology between the molecules produced by all eukaryotes from bacteria to man (Young and Elliott, 1989). For example, GroEL, a 60 kDa heat-shock protein (hsp) produced by stressed bacteria, shows close similarity with the homologous hsp produced by widely different organisms, such as mycobacterial hsp65 and mammalian hsp60 (Shinnick 1991). The cross-reactivity of the antibodies generated against the homologous Hsp60 and Hsp65 proteins produced by bacteria, parasites and mammals and the immunogenicity of Hsp60 and Hsp65 to the T lymphocyte system has attracted considerable interest among the immunologists. Besides the well-known recognition of mycobacterial Hsp65 by γδ T-cells (Kaufmann et al, 1987; Soderstrom et al, 1990), γδ T-cells specific for Hsp60 have been implicated in diseases with a possible autoimmune basis such as arthritis (van Eden et al, 1988; Gaston et al, 1989), Behcet's disease (Hasan et al, 1996), diabetes (Elias et al, 1990), coeliac disease (Halstensen et al, 1989) and multiple sclerosis (Selmaj et al, 1991; Selmaj et al, 1992). Additionally, antibodies to Hsp65 has been observed in patients with superficial candidiasis (Ivanyi and Ivanyi, 1985).

The immune mechanisms of bacterial and parasitic immune response mediated by Hsp60 activation may involve both γδ T-cells and macrophages since Hsp60, expressed by stressed macrophages, has been shown to be recognized by γδ T cells (Koga et al, 1989). Hsp60 may also mediate immune responses to mitogenic bacterial toxins (Fast et al, 1989) since Hsp60 expression is induced by mitogens and lymphokines (Ferris et al, 1988; Kiessling et al, 1991).

Recent interest is centered on γδ T-cells autoreactive with self Hsp60 as the possible mechanism in autoimmune diseases. Studies by O'Brien et al, using a panel of murine γ/δ T-cell hybrids, observed “spontaneous” reactivity of the γδ T-cells, with production of IL-2 in the absence of added antigen, suggesting possible preactivation of the TCRγ/δ by autologous Hsp60. These presumed preactivated γδ hybrids utilized the Vd6 regions, which, in the absence of added antigen, is in keeping with TCRγ/δ specificity to autologous Hsp60 (O'Brien et al, 1989). Once activated, these hybrids were observed to be more prone to respond to other Hsp60 homologues (O'Brien et al, 1989).

A selective response of γδ T-cell hybridomas to orthomyxovirus-infected cells, but not to vaccinia or Sendai virus is reported by Ponniah et al (1996). The spectrum of orthomyxoviral antigens has never been shown to be recognized by αβ T-cell subsets. Based on previous observations that Hsp60-reactive hybridomas responded to influenza-virus infected cells, and that immunofluorescent studies demonstrated the presence of increased Hsp60 in influenza-infected cells, but not in Sendai virus- or vaccinia virus-infected cells, Ponniah et al (1996) suggested that Hsp60 may be the target antigen responsible for stimulating the γδ T-cell response (Ponniah et al, 1996).

Recently Yi et al (1997) investigated the basis for the correlation of immunopathologic sequelae with immune responses to the Chlamydia trachomatis Hsp60. Groups of CBA mice were immunized with recombinant mouse Hsp60, recombinant chlamydial Hsp60, or both proteins. Immunization with mouse Hsp60 alone produced T-cells which secreted high levels of IL-10, but did not proliferate. However, immunization with both mouse Hsp60 and chlamydial Hsp60 resulted in strong T-cell proliferation, much lower levels of IL-10 (TH2 cytokine) production, and much higher levels of interferon-γ (TH1 cytokine) production (Yi et al, 1997), again demonstrating the synergistic enhancement of a two-stimulus response.

Accumulating evidence of involvement of Hsp60 and γδ T-cells in chronic inflammatory diseases other than atherosclerosis suggests that similar mechanisms may exist for multiple diseases. Thus, the role of γδ T-cells and bacterial Hsp65 and its human homologue Hsp60 (Jindahl et al, 1989), has been increasingly recognized in a variety of diseases. These include inflammatory arthritis (Brennen et al, 1988; Smith et al, 1988; Res et al, 1991), multiple sclerosis (Selmag et al, 1991; Selmag et al, 1992), and pulmonary sarcoidosis (Balbi et al, 1990), among others.

Evidence for the Role ofγδ T-Cells in Atherogenesis

The possible involvement of γδ T-cells in atherogenesis has been raised from the observations that the inflammatory cellular population in atherosclerotic lesions is enriched in γδ T-cells (Kleindienst et al, 1993). The higher percentage of γδ T-cells in intimal streaks compared to mature atherosclerotic lesions suggests that γδ T-cells may be involved in the early development of the atherosclerotic plaque. Suggestive evidence is indicated by chronological events in studies of injured arteries and atherosclerotic lesions at various stages of maturity, as well as other pertinent although indirect findings. Chronologically, the γδ T-cell is the earliest inflammatory cell observed both in the adventitia and the intima after arterial injury (Heng et al 1994; Heng et al, 1997). The γδ T-cells were observed in injured arteries as early as 4-24 hours following arterial injury induced by arterial ligation followed by re-establishment of blood flow i.e., reperfusion. In these studies, the appearance of γδ T-cells precedes that of their αβ counterpart, and are postulated to play a role in initiating the inflammatory response in injured arteries (Heng et al, 1997).

Hsp60 as Possible Antigens Activating γδ T-Cells in Atherogenesis

Of the two T-cell lineages, the γδ T-cell lineage is recognized as the primary responder to Hsp65 produced by stressed cells. Hsp65 from mycobacterial sources has been shown to be recognized by γδ T-cells (Haregewoin et al, 1989). Recent technical advances have enabled investigators to study the clonal phenotype generated in response to antigenic stimulation of various T cells. Human γδ T-cells of the Vγ9/Vδ2 clonal phenotype are shown to respond to antigenic stimulation by GroEL/Hsp60 homologue on the surface of Daudi cells ( Fisch et al, 1990). In addition, clones of Vγ1/Vδ6 T-cells responsive to Hsp60 in skin cells have been identified (Reardon et al 1994), suggesting antigen-specific clonal proliferation. O'Brien et al found that in the skin, the majority, if not all, the γδ T-cells respond to Hsp60 (O'Brien et al, 1992), suggesting clonal expansion, presumably in response to specific antigens presented in the skin (Asarnow et al, 1988; Havran et al, 1989). It is possible that although largely homologous, small differences between the epitopes of various Hsp60/Hsp65 homologues from bacteria to human may account for differences in antigen-specific TCRγδ recognition and different TCR clonal rearrangements. These differences are clearly apparent when one examines the structure of the epitope recognized by ML30, the monoclonal antibody directed against GroEL/Hsp60/Hsp65 from various sources. This monoclonal antibody reacts against an epitope on M. leprae Hsp60 within residues 311322 (Anderson et al, 1988). As shown below in Figure 5, the suspected antigenic determinant may be a tetrapeptide DMAI, which corresponds to residues 315-318. As is seen in Figure 5, the tetrapeptide DMAI of M. leprae and M. tuberculosis is shared with human Hsp60 but not present in E. coli GroEL/Hsp60. The ML30 monoclonal antibody, directed against the tetrapeptide DMAI from M. leprae Hsp65, will cross-react against Hsp65 from M. tuberculosis and human Hsp60, but not against E. coli Hsp60.

Figure 5. This figure compares the sequential epitope of M.

Figure 5

This figure compares the sequential epitope of M. leprae Hsp65 with the corresponding epitopes in the homologous Hsp65 of M. tuberculosis, human Hsp60 and E. coli GroEL.

A basis for the variability in the Hsp60-specific TCRγδ clones may lie in recognition of minor differences between the different Hsp60 homologues from different sources, i.e. bacterial vs human (Munk et al, 1990). Another basis for the variability in the Hsp60-specific γδ T-cell clones may lie in the recognition of different lengths of HSP60 peptide-epitopes, which may arise when Hsp60 is presented to the TCRγδ with or without the involvement of MHC antigens. There is some evidence that γδ T-cells recognize different lengths of Hsp60 peptides or even the whole Hsp60 protein. The Hsp60-reactive γδ T-cells cells in liver and spleen show differences in TCR junctions, suggesting that different sizes of Hsp60 epitopes are recognized by these cells (Roark et al, 1993). Furthermore, studies suggest that γδ T-cells may recognize the Hsp60 protein rather than processed peptides (Fu et al, 1994; Chien 1996). There is also evidence that inorganic side chains and nonpeptide molecules may also be stimulatory to the TCRγδ (Schoel et al 1994; Bukowski et al, 1995). The above nuances in antigen recognition provide the basis for variability in Vg and Vd clonal rearrangements observed among the γδ T-cells.

Preferential Expansion ofγδ T-Cells in Response to Hsp60

T lymphocytes bearing TCRγ/δ have been shown to recognize Hsp60 (Haregewoin et al, 1989; Born et al, 1990; Soderstrom et al, 1990). The results of in vitro experiments examining the effects of stress such as heat shock on T-cell induction and selection carried out by Rajasekar et al (1990) support the probability of self-originated heat shock proteins as the inducer of specific T-cell dependent pathways inatherogenesis. These investigators observed a selective proliferation of γδ T-cells after incubating cell preparations for 30 mins at 42°C. By also showing that the preferential enrichment of γδ T-cells induced by heat shock, these investigators show that γδ T-cells are stimulated by heat shock proteins (presumably Hsp60) produced by stressed cells.

Preferential Expansion of γδ T-Cells in Response to Hsp60 Can Occur in the Absence of IL-2: Relevance to Atherogenesis

The preferential expansion of γδ T-cells in response to Hsp60 has been studied by Hermann et al (1992). Cloning experiments of T-cell lines showed that stimulation with human Hsp60 alone produced a cell-line consisting predominantly of γδ T-cells (Hermann et al, 1992). In these experiments, cloning of T-cell lines was performed using phytohemagglutinin as a comitogen and IL-2 as a growth factor. Kinetic studies showed an expansion of TCRγδ + lymphocytes in Hsp60-stimulated synovial fluid mononuclear cells, which was not dependent on the addition of exogenous IL-2. The expanded γδ T-cells were found to be in part CD4-CD8-, but in part also CD8+ (Hermann et al, 1992). The CD8 positivity of some γδ T-cells supports current observations that the CD8 molecule serves as an accessory molecule in γδ T-cells (Bucy et al, 1989), and may be present in some activated γδ T-cells (Goodman et al, 1988). These observations emphasize the fact that γδ T-cells are capable of responding specifically to Hsp60, and of expanding clonally in the absence of IL-2. These properties support the premise that in the arterial response to injury, the γδ T-cells may be the subset that responds to Hsp60 produced by stressed cells.

Evidence of Involvement of Hsp60 andγδ T-Cells in Atherogenesis

Although the TCR Vγ and Vδ clonal phenotypes have not been analyzed in early atherosclerotic lesions, there is much indirect data suggesting that antigens, in particular heat shock proteins (hsp), are present in atherosclerotic lesions, and may function antigenically to activate γδ T-cells. Elevated levels of serum antibodies to Hsp60 have been reported in patients with carotid atherosclerosis (Xu et al, 1993). These investigators also induced atherosclerosis in normocholesterolemic rabbits by immunization with Hsp60 (Xu et al, 1992), providing evidence of the pivotal role of Hsp60 in initiating atherogenesis. The link between Hsp60 and γδ T-cells is provided by observations of both Hsp60 and γδ T-cells in atherosclerotic lesions (Kliendienst et al, 1993). In addition, Hsp65 and γδ T-cells are shown to colocalize in experimental atherosclerotic lesions of rabbits specifically responding to hsp65 (Xu et al, 1993). In line with the response to injury hypothesis of atherogenesis (Ross, 1993) are observations by our laboratory of the presence of Hsp60 and activated γδ T-cells within hours of arterial injury (Heng 1994; Heng 1997). It is pertinent at this point to present these findings in greater detail.

In human arteries dissected from surgical specimens, we observed early induction of Hsp60 (the human homologue of bacterial Hsp65) in ligated but not in nonligated arteries (Heng 1994). The presence of Hsp60, which was observed in close apposition with aggregated Hsp60, was associated with infiltration of activated (HLA-DR+) γδ T-cells. The tannic acid-stained protein was identified as Hsp60 by immunogold-labeled monoclonal antibodies using immunoelectron microscopic labeling techniques. In this study, human mesenteric arteries ligated during abdominal surgery were used. The duration of arterial ligation, which corresponded to the length of the surgery, varied from 30 mins to 4 hrs. After removal of the surgical specimens, the ligated arteries were dissected, and processed for electron microscopy and immunohistochemistry. Immunohistochemical preparations confirmed the presence of dendritic CD3+ T-cells, which were also TCRγ/δ+, in the process of infiltrating the arterial intima of ligated arteries within hours of ligation (fig. 6a). Similar findings were also observed in ligated rat arteries (fig. 6b; Heng et al, 1995).

Figure 6. Immunohistochemical preparation of a ligated human artery 4 hours following arterial ligation.

Figure 6

Immunohistochemical preparation of a ligated human artery 4 hours following arterial ligation. Note the presence of a single dendritic TCRγ/δ+ lymphocyte (arrowhead) at the luminal-intimal junction at the point of infiltrating the arterial (more...)

Ultrastructural preparations showed the presence of dendritic γδ T cells within the intima and adventitia of the ligated arteries. These cells were characterized by one or more dendritic processes (fig. 7) a lymphoid nucleus with abundant dense chromatin, and the presence of dense perforin-containing cytoplasmic granules (fig. 7). The γδ T-cells cells were observed to colocalize with a tannic acid-stained protein in the injured arteries. This tannic acid-stained protein was identified as Hsp60 by immunogold Au linked to cross-reactive anti-Hsp65 monoclonal antibodies (fig.8; Heng et al, 1994). We observed the dendritic processes of the γδ T-cells to be in close apposition with the tannic acid stained Hsp60 aggregates (fig. 9; fig.10; Heng 1994; Heng et al, 1995), supporting the notion that direct surface contact with the Hsp60 is important in antigen-recognition (Fu et al, 1994; Chien et al, 1996).

Figure 7. Ultrastructure of injured human artery within 4 hours following arterial ligation.

Figure 7

Ultrastructure of injured human artery within 4 hours following arterial ligation. Note the presence of a dendritic T-cell (DT) with long dendritic processes (D), lymphoid nucleus with dense chromatin pattern and dense cytoplasmic granules (G). Magnification (more...)

Figure 8. Immunoelectron microcopy of injured human artery showing immunogold labeled Hsp60 (arrow) colocalizing with a fibrillar tannic acid stained protein (HSP).

Figure 8

Immunoelectron microcopy of injured human artery showing immunogold labeled Hsp60 (arrow) colocalizing with a fibrillar tannic acid stained protein (HSP). Magnification: 135,000X.

Figure 9. Ultrastructure of an injured rat artery 24 hours following arterial ligation.

Figure 9

Ultrastructure of an injured rat artery 24 hours following arterial ligation. Note the presence of dendritic γδ T-cells (DT) with lymphoid nuclei and dense cytoplasmic granules (G) and long dendritic processes. Note the direct contact (more...)

Figure 10. Ultrastructure of an injured human artery 4 hours following arterial ligation.

Figure 10

Ultrastructure of an injured human artery 4 hours following arterial ligation. Note the presence of dendritic processes (D) of dendritic γδ T-cells in direct contact with tannic acid stained HSP60 (HSP). Magnification: 40,000X.

Observations of γδ T-cells at the luminal-intimal junction of injured arteries (fig. 6a,b; Heng 1994) point to the circulating γδ T-cells population as the source of the γδ T-cells infiltrating the arteries. It was observed that the dendritic processes of the γδ T-cell population infiltrating the tissues were better developed (fig. 6a, fig. 7, fig. 11) than the dendritic processes of circulating γδ T-cells (fig. 6b). These observations are consistent with similar observations of the tissue dendritic subset of γδ T-cells previously described (Grossi et al, 1989). That these infiltrating dendritic γδ T-cells are activated is shown by the detection of IL-2 receptors on these cells (Heng 1994; Heng 1997). It was also noted that the presence of activated γδ T-cells within the intima of injured arteries preceded vascular smooth muscle cell migration (Heng et al, 1995; see also Figure 8.1 in Chapter 8).

Figure 11. Ultrastructure of an injured human artery 4 hours following arterial ligation.

Figure 11

Ultrastructure of an injured human artery 4 hours following arterial ligation. Note a dendritic T-cell (DT) with lymphoid nucleus, dense cytoplasmic granules (G), and multiple dendritic processes (D). Magnification: 25,000X.

We hypothesize that the hypoxic injury induced by arterial ligation results in the production of Hsp60 by the injured artery and γδ T-cell activation. Infiltration of γδ T-cells into sites of arterial injury secondary to expression of adhesion molecules induced by arterial injury (see Chapter 7), leads to interaction of dendritic γδ T-cells with Hsp60. That these events are followed by activation of γδ T-cells is indicated by the expression of IL-2 receptors by these cells. These findings may have several far reaching implications, the most important of which is that hypoxic injury triggers a Hsp-dependent γδ T-cell mediated immune response, which results in the production of inflammatory cytokines known to be produced by activated γδ T-cells, including interferon-γ, IL-1 and TNFα. It has been shown that interferon-γ and TNFα act synergistically to further induce hsp60 expression in monocyte cell lines (Jindal et al, 1989). The effect on Hsp60 expression by the combination of interferon-γ and TNFα exceeds that induced by heat shock or interferon-γ acting singly (Jindal et al, 1989). These results are summarized in Table 1. Heat shock-activated γδ T lymphocytes and macrophages secrete cytokines, which activate other immune and nonimmune target cells. The relationship of cytokines to receptor-mediated signaling and target cell activation is discussed in Chapter 4-6.

Table 1. Inducible Hsp60 mRNA and protein expression in monocytes.

Table 1

Inducible Hsp60 mRNA and protein expression in monocytes.

The activated γδ T-cell is capable of producing a wide variety of cytokines and growth factors, including IL-1, IL-2, interferon-γ, TNFα, TNFβ and granulocyte-monocyte colony stimulating factor, GM-CSF (Ciccone et al, 1988; Takashima et al, 1992; Bergstresser et al, 1993). Cells with cytotoxic properties have been shown to contain the γ chain (Brenner et al, 1987). Enzymes associated with cytotoxic and cytolytic function found in γδ T cells include perforin and serine esterases, are detected within human γδ T-cells (Koizumi et al, 1991), suggesting that these cells are capable of cytotoxic and cytolytic function. In addition, the array of cytokines, such as interferon-γ, IL-1 and TNFα and TNFβ secreted by the activated γδ T-cells (Ciccone et al, 1988; Takashima et al, 1992; Bergstresser et al, 1993) act to prime other inflammatory cells including macrophages, to respond to other injurious or mitogenic stimuli. It is known, for example, that TNF production in response to endotoxin can be augmented by the addition of interferon-γ (Burchett et al, 1988), further emphasizing the effects of “priming” by cytokines to achieve the magnitude of cytokine production by activated macrophages in a “two-stimuli” response. In addition, these cytokines prime nonimmune targets such as reactive oxygen species and smooth muscle cells to secrete chemokines, which serve to recruit other T cell subsets and macrophages to sites of vascular injury.

Antigenic Role of Oxidized LDL in Atherogenesis

The presence of oxidatively modified low density lipoprotein (LDL) in atherosclerotic lesions has been well established (Yla-Herttuala et al, 1989). There is evidence that T cells from human atherosclerotic plaques are activated after exposure to oxidized LDL (Stemme et al, 1995). However, since there is no evidence that oxidized LDL contains epitopes that actually bind to the TCR, it is possible that Hsp60 generated by oxidative stress from lipid peroxidation may mediate this response. In support of this premise are observations that oxidative stress stimulates the production of heat shock proteins through the induction of heat shock factor (HSF) phosphorylation, leading to HSF-dependent gene transcription (Liu and Thiele, 1996; see also Chapter 8, Fig. 8.1).

Other studies have suggested that a humoral immune response involving oxidized LDL may aggravate atherosclerosis. Palinsky reported that antibodies may be produced against epitopes generated during oxidative modification of LDL (Palinski et al, 1990). There is also evidence for the involvement of complement activation associated with cholesterol accumulation in experimental atherosclerosis ( Seifert et al, 1989). However, B cells are rare in atherosclerotic lesions, and there is little evidence for a predominant primary antibody-dependent cell-mediated response in the initiation of the atherosclerotic process.

Other Potential Antigens: Possible Precipitating Factors in Atherogenesis

MHC Class I-b Molecules Present Cytoplasmic, Nuclear, Mitochondrial, Viral and Bacterial Proteins to T-Cells for Recognition

Besides studies indicating recognition of Hsp60/65 by γδ T-cells (Born et al, 1990), a number of studies suggest the possibility that other peptides may also be recognized by γδ T-cells. The preponderance of studies provide evidence suggesting that alloreactivity reflects the presentation of self peptides by class I allomorphs (Lechler et al, 1991; Crumpacker et al, 1992; Villadangos et al, 1992; Sherman et al, 1993). Since it has been shown that cytoplasmic, nuclear,mitochondrial, viral and bacterial proteins may serve as MHC class I-b ligands (reviewed by Shawar et al 1994), it may be relevant at this point to review MHC class I-b molecules and their potential ligands. Of interest are studies showing that γδ T-cells recognize antigens restricted by certain class Ib MHC molecules, such as Qa-1 (Vidovic et al, 1989), Qa-2 (Okazaki et al, 1993), T22 and TL (Ito et al,1990). On the other hand, ligands of other MHC class I-b molecules, such as H-2M3a, are recognized byαβT-cells (Loveland et al, 1990; Shawar et al, 1991; Wang et al, 1991). The H-2M3 encoded receptor presents N-formylated peptides from infectious organisms, such as Listeria monocytogenes to cytotoxic T lymphocytes (Pamer et al, 1992); Shawar et al, 1994).

TL ligands are essentially peptides and viral antigens. Clinical relevance of the association of the MHC class I-b molecule, TL, and γδ T-cells is shown by reports of TL-specific γδ T-cells in small intestine(Eghtesady et al, 1994). Eghtesady et al demonstrated that TL gene product can present peptides to intestinal epithelial γδ T-cells, and that this response was specific and was mediated by γδ T-cells expressing Vγ5. AntiTL monoclonal antibody was effective in blocking the response (Eghtesady 1994). TL encoded molecules are involved in the processing and presentation of viral antigens (Milligan et al, 1991). The concept of virus-induced atherosclerosis dates back to the late 1970s with studies of Fabricant et al (Fabricant et al, 1978). There is, in particular, an association between infection with the herpes family of viruses, in particular herpes simplex types 1 and 2 and cytomegalovirus, to atherosclerosis (Sortie et al, 1994). Several studies have also demonstrated a correlation between cytomegaloviral infection and accelerated atherosclerosis in heart transplant patients (Grattan et al, 1989; MacDonald et al, 1989; Koskinen et al, 1993; Paavonen et al, 1993). Evidence of stimulation of activated T lymphocytes by cytomegalovirus-infected allogeneic reactive oxygen species was reported by Waldman et al (1992).

Hsp65, on the other hand, appears to be the ligand of Qa-1. It is of interest that the cell surface expression of the MHC class I-b molecule, Qa-1, is higher after heat shock treatment or after incubation with hsp65. In addition, a synthetic peptide corresponding to Hsp181-195 of M. bovis mimicked the effect of heat shock or tryptic digest of Hsp65, suggesting that Hsp65 may be the ligand of Qa-1 (Imani et al, 1991). This finding provides another mechanism for a possible role of Hsp60/65 in stress-inducedatherogenesis.

CD1 Protein Family of Antigen Presenting Molecules Present Lipids and Glycolipids for T-Cell Recognition

Several proteins encoded by genes unlinked to MHC genes show 25-30% sequence homology with class I MHC molecules and associate noncovalently with β2 microglobulin (reviewed by Shawar et al 1994). These include the CD1 protein, IgG Fc receptor in intestinal epithelial cells of neonatal mice and rats (FcRn), and zinc-α2-glycoprotein (ZAG). CD1 is expressed preferentially on all antigen presenting cells, including dendritic cells, macrophages and γδ T-cells. Of the 5 known isoforms (CD1ae), CD1a, b and c are expressed at high levels on monocytes cultured in vitro with a combination of GM-CSF and IL-4, and restricts the response of T-cells to a variety of foreign lipids and glycolipids(Porcelli & Modlin, 1999). CD1c is a target recognition structure for lysis of CD1c-expressing tumor cells by γδ T cells (Faure et al 1990), and CD1b functions in the same way for CD4-CD8-αβT-cells(Thomssen et al 1995). CD1b-restricted T-cells recognize lipoarabinomanan (LAM), a mycobacterial cell wall constituent. LAM belongs to a family of glycosylphosphatidyl inositols, and is composed of a hydrophobic lipid-containing phosphatidylinositol group attached to a large hydrophilic heteropolysaccharide (Prinzis et al 1993).

The possible role of CD1 and CD1 restriction in antigen recognition in atherosclerotic arteries is becoming increasingly recognized. Vascular dendritic cells (VDC), which are members of a family of dendritic/antigen-presenting cells, reside in the intima of large arteries. These cells express CD1a, as well as HLA-DR, ICAM1, VCAM-1 and S-100 protein. Their numbers are increased in atherosclerotic lesions, and are found to colocalize with T-cells (Bobryshev & Lord, 1998). Immature dendritic cells lack the requisite costimulatory signals, such as CD40, CD154 and CD86, for T-cell activation. After CD1a-dependent stimulation by microbial or inflammatory products, dendritic cells become differentiated (mature), upregulate costimulatory molecules, such as CD40, CD154 and CD86, and become more mobile (activated). They then prime T-cells, interact with other cells, such as macrophages for cytokine release and B cells for antibody production, and target cells for lytic activity (Banchereau & Steinman 1998). Thymic dendritic cells and T-cells develop from a common precursor (Ardavin et al, 1993). Thus, it is not surprising that CD40-ligated dendritic cells express CD8+ and acquire a lymphoid phenotype (Anjuere F et al 2000).

Dendritic cells have been shown to acquire antigen from apoptotic cells, which in turn trigger dendritic cell maturation and antigen presenting function (Albert et al 1998; Rovere et al, 1998). CD1 molecules recognize lipid antigens (Porcelli and Modlin, 1999; Jackman et al, 1999), which are presumed to be derived from the disintegrating cell membranes of apoptotic cells (Shamshiev et al, 1999). The role of dendritic cells in atherosclerotic lesions is increasingly recognized in view of their potential priming effect on the initiation of the immune response (Melian et al, 1999). These authors have shown that foam cells arising from CD1+ monocytes are able to stimulate CD1-restricted responses in T-cells.

Advanced Glycosylation End (AGE) Products as Possible Antigens

There is evidence that advanced glycosylation end (AGE) products are present in atheromas and cardiac tissue in diabetics using immunocytochemical techniques (Nakamura et al, 1994). Advanced glycosylated sites on altered collagen, damaged as a result of lipid peroxidation (Bucala et al, 1993), covalently bind oxidized LDL, and are thought to serve as a trap for LDL (Brownlee et al, 1985). It is possible that AGE products may aggravate atherogenesis by accumulating LDL for free radical modification, released for example by myeloperoxidase (Daugherty et al, 1994)from macrophages and/or neutrophils, leading to the accumulation of oxidized LDL in atherosclerotic tissues. Increased uptake of oxidized LDL via the increased expression of the scavenger receptor on macrophages (Fogelman et al, 1981) may contribute to foam cell development in atherosclerotic lesions.

Although AGE products are linked to gene activation (Schmidt et al, 1994), and chemotaxis of monocytes into atherosclerotic lesions (Kirstein et al, 1990), epitopes for TCR recognition on AGE products have not been identified. Since AGE products are particularly prominent in diabetics, it is also possible that these products may represent the degenerate products of oxidative tissue injury. The detection of AGE in both diabetic and atherosclerotic tissues may also point to a link between diabetes and atherosclerosis.

Role of Multiple Stimuli in the Regulation of the Magnitude and Chronicity of the γδ T-Cell Response

Heat shock proteins and their antibodies are detected in situations of arterial wall stresses, such as hypertension (Fostergard et al, 1997), injurious stimuli, including hypoxia and brief ischemia (Knowlton 1991; Li 1992), and reactive oxygen species (Donati 1990). These proteins have also been found in atherosclerotic arteries (Berberian et al, 1989; Xu et al, 1993). The stress protein, Hsp60, has been shown to stimulate T-cells bearing TCRγδ (Haregewoin et al, 1989; O'Brien et al, 1989). It has been proposed that Hsp60 may be the dominant self-antigen in the selection of γδ T-cells (Bell 1995). The possibility of γδ T-cells responding to antigens other than Hsp60 is shown by the observation of preferential expansion of γδ T-cells after stimulation with live, but not heat-killed Yersinia (Hermann et al, 1992). These additional antigens may, together with Hsp60, serve to synergistically enhance the preferential expansion of γδ T-cells.

The notion of the synergistic effect of dual stimuli in regulating the magnitude of the self Hsp60-selective γδ T-cell response in atherogenesis, is supported by the observation that pre-exposure to mycobacterial antigens (PPD) in vivo resulted in a greater enrichment of γδ T-cells (Rajasekar et al, 1990). These investigators also found that self heat shock (presumably through Hsp60) is as important as antigenic priming in the synergistic enrichment of γδ T-cells. They found that lymphocytes from draining lymph nodes primed with PPD in vivo produced a population consisting of 65% γδ T-cells in heat-shocked lymphocytes, compared with 22% in nonheat-shocked lymphocytes (Rajasekar et al, 1990).

Further evidence that multiple stimuli contribute to the chronicity of the atherosclerotic response is provided in a recent study by Xu et al (1996). These investigators had previously demonstrated that arteriosclerotic changes can be induced in normocholesterolemic rabbits by immunization with mycobacterial Hsp65 (Xu et al, 1992). In a recent study, these investigators also showed that the institution of a hypercholesterolemic diet caused the prolongation of the atherogenic response to Hsp65 immunization in normocholesterolemic rabbits (Xu et al, 1996). In contrast, in the absence of a second stimulus, e.g., hypercholesterolemia, the tendency is for the induced arteriosclerotic lesions to regress (Xu et al, 1996), thus resembling the homeostatic (negative feedback) wound healing response after a single injury.

It is thus proposed that the initial changes resulting from the early immune response induced by Hsp60 and γδ T-cells are at first reversible. It is only the presence of additional risk factors, such as hypercholesterolemia, hypertension, diabetes, smoking, microbial/viral infections and heart transplantation, that lead to the development of severe, irreversible atherosclerotic plaques and arteriosclerosis in injured arteries (Ross 1993; Wu et al, 1992; Koskinen et al, 1993; Paavonen et al, 1993; Sorlie et al, 1994; Wick et al, 1995; Frostegard et al, 1996; Xu et al, 1996).

Microbial products may serve as antigens in two ways. First, bacterial cell wall products such as lipopolysaccharides and chlamydial antigens have been shown to be antigenic (Libby et al, 1999). Alternatively, microbes may produce also produce hsp60, as shown by the detection of chlamydial hsp60 in human atheroma, and its regulation of TNFα production (Kol et al, 1998). In addition, both microbial cell walls (e.g., LPS) and microbial hsp60 may act synergistically to enhance the immune response. Kol et al observed that CD14, a monocyte receptor for LPS. is essential for Hsp60 activation of mononuclear cells (Kol et 1 al, 2000). Both human and microbial Hsp60 have been shown to activate reactive oxygen species, smooth muscle cells and macrophages by triggering the activation of

  1. NF-kB complexes containing p65 and p50 Rel proteins,
  2. proinflammatory cytokines, such as IL-6), and 3. adhesion molecules such as E-selectin, ICAM-1 and VCAM-1 (Kol et al, 1999).

Other antigens, such as oxidized LDL, also act synergistically with inflammatory cytokines, such as TNFα, and produce costimulatory and additive effects in increasing endothelial cell expression of membrane type 1-matrix metalloproteinase (Rajavashisth et al, 1999). Oxidized lipids activate endothelial peroxisomal proliferator activated receptor-γ (PPARγ), a ligand-activated transcriptionfactor), resulting in increased expression of plasminogen activator inhibitor-1 (PAI-1), leading to increased thrombotic tendency (Marx et al, 1999). In addition, macrophage and platelet activation and release of their respective chemotactic cytokines and growth factors play an important and perhaps costimulatory role. These risk factors provide the additional stimuli which enhance the magnitude and the longevity of the T-cell mediated immune response triggered by Hsp60. Thus, it may be considered that the Hsp60-T-cell response in atherogenesis may represent a protective response gone awry.

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