Alternative titles; symbols
HGNC Approved Gene Symbol: CD4
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,789,528-6,820,799 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | Immunodeficiency 79 | 619238 | Autosomal recessive | 3 |
| OKT4 epitope deficiency | 613949 | 3 |
CD4 is a cell surface glycoprotein that is expressed on subsets of thymocytes and mature T lymphocytes, as well as on monocytes and macrophages. CD4 plays an important role in T-helper (Th) cell development and activation (summary by Zeitlmann et al., 2001).
In a study of the structure and expression of human and mouse T4 genes, Maddon et al. (1987) found that T4 RNA is expressed not only in T lymphocytes, but also in B cells, macrophages, and granulocytes. It is also expressed in a developmentally regulated manner in specific regions of the brain. The authors suggested the possibility, therefore, that T4 plays a more general role in mediating cell recognition events than merely those of cellular immune response. Since the T4 molecule serves as a receptor for the human immunodeficiency virus (HIV; see 609423), this information may have relevance in relation to the manifestations of AIDS.
Littman (1987) reviewed CD4 gene structure.
Ansari-Lari et al. (1996) generated the genomic sequence of the human CD4 gene and its neighboring region on chromosome 12p13 using the large-scale shotgun sequencing strategy. A total of 117 kb of genomic sequence and approximately 11 kb of cDNA sequence was obtained. They identified in this sequence 6 genes with known functions, including CD4. Using a battery of strategies, the exon/intron boundaries, splice variants, and tissue expression patterns of the genes were determined.
With in situ hybridization, Isobe et al. (1986) regionalized the CD4 gene to chromosome 12pter-p12. By genomic sequence analysis, Ansari-Lari et al. (1996) mapped the CD4 gene to chromosome 12p13.
Gross (2011) mapped the CD4 gene to chromosome 12p13.31 based on an alignment of the CD4 sequence (GenBank BT019791) with the genomic sequence (GRCh37).
CD4 binds to relatively invariant sites on class II major histocompatibility complex (MHC) molecules outside the peptide-binding groove, which interacts with the T-cell receptor (TCR). CD4 enhances T-cell sensitivity to antigen and binds to LCK (153390), which phosphorylates CD3-zeta (CD3Z; 186780). Instead of clustering in a cap at the interface with an antigen-presenting cell (APC), some signaling molecules involved in T-cell recognition segregate into distinct areas to form a SMAC (supramolecular activation cluster), contributing to the immunologic synapse (see Grakoui et al. (1999)). Using T-cell lines transfected with green fluorescent protein-fused CD4 or CD3Z and 3-dimensional video microscopy, Krummel et al. (2000) showed that in response to peptide-loaded APC, CD3Z and CD4 initially cluster in the contact area between the T cell and APC coincident with intracellular calcium mobilization. Stable immunologic synapse formation was modulated by peptide concentration and compromised by blocking the calcium increase or cytoskeletal rearrangement. The authors determined that CD3Z remains at the center of the interface while CD4 moves to the periphery. Blocking with anti-TCR prevented CD3Z accumulation and inhibited calcium mobilization. The data suggested that instead of stabilizing TCR-MHC complexes, CD4 functions to initiate or augment the early phase of T-cell activation.
By yeast 2-hybrid analysis, Zeitlmann et al. (2001) found that the cytoplasmic tail of CD4 interacted with ACP33 (608181). Using coimmunoprecipitation experiments, they confirmed that endogenous CD4 interacted with ACP33 in an ACP33-transfected CD4-positive T-cell line. By analyzing the interaction between various truncation and point mutants, they determined that the last 2 conserved hydrophobic amino acids at the C terminus of CD4 and ser109 within the alpha/beta fold of ACP33 were required for the interaction. Truncation of the last 2 amino acids of CD4 enhanced T-cell receptor (see 186880)-induced T-cell activation, suggesting that ACP33 is a negative regulator of CD4 activity. The CD4-ACP33 complex could also coprecipitate LCK. There was no direct interaction between ACP33 and LCK, indicating that ACP33 and LCK interact independently and simultaneously with CD4.
Although CD4 was identified initially as the cellular receptor for HIV, several lines of evidence indicated that expression of CD4 alone was insufficient to confer susceptibility to infection by the virus. Specifically, HIV did not infect mouse cells transfected with a human CD4 expression vector or mice transgenic for the expression of human CD4. Furthermore, although HIV binding and internalization can be mediated by CD4 acting together with one of several members of the chemokine receptor superfamily, CCR5 (601373) appears to be the critical coreceptor used by HIV in the initial stages of infection. However, because mouse CCR5 differs significantly from human CCR5, it cannot function as a coreceptor for HIV, and thus, expression of human CD4 alone is insufficient to permit entry of HIV into mouse cells. Browning et al. (1997) found that mice transgenic for both CD4 and CCR5 are susceptible to HIV infection.
In transgenic mice carrying the human CD4 gene, Buttini et al. (1998) found that human CD4 is expressed on microglia, the resident mononuclear phagocytes of brain. Normally there is no neuronal damage. Activation of brain microglia by peripheral immune challenges elicited neurodegeneration in human CD4 mice but not in nontransgenic controls. In postmortem brain tissues from AIDS patients with opportunistic infections, but without typical HIV encephalitis, human CD4 expression correlated with neurodegeneration. Buttini et al. (1998) concluded that human CD4 may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system (CNS). The important role of human CD4 expression on microglia/macrophages creates a pathogenetic link between the immune system and the CNS.
The Nef protein of primate lentiviruses downregulates the cell surface expression of CD4 through a 2-step process. First, Nef connects the cytoplasmic tail of CD4 with adaptor protein complexes (AP), thereby inducing the formation of CD4-specific clathrin-coated pits that rapidly endocytose the viral receptor. Second, Nef targets internalized CD4 molecules for degradation. Piguet et al. (1999) showed that Nef accomplishes this second task by acting as a connector between CD4 and the beta subunit of the coatomer protein complex (COPB; 600959) in endosomes. A sequence encompassing a critical acidic dipeptide, located nearby but distinct from the AP-binding determinant of HIV-1 Nef, is responsible for COPB recruitment and for routing to lysosomes. A novel class of endosomal sorting motif, based on acidic residues, was thus revealed, and COPB was identified as its downstream partner.
Using immunofluorescence microscopy, Yeaman et al. (2004) examined expression of the HIV receptors CD4 and galactosylceramide (see GALC; 606890) and the HIV coreceptors CXCR4 (162643) and CCR5 in ectocervical specimens from hysterectomy patients with benign diseases. CD4 expression was detected on epithelial cells at early and midproliferative stages of the menstrual cycle, whereas galactosylceramide expression was uniform in all stages of the menstrual cycle. CXCR4 was not detected on ectocervical epithelial cells, whereas CCR5 was expressed on ectocervical epithelial cells at all stages of the menstrual cycle. CD4-positive leukocytes were present in the basal and precornified layers of squamous epithelium during early and midproliferative phases of the menstrual cycle, but were absent in later proliferative phases and the secretory phase; the presence of CD4-positive leukocytes was not related to inflammation. Yeaman et al. (2004) concluded that HIV infection of the ectocervix most likely occurs through galactosylceramide and CCR5.
Using 3-dimensional fluorescence microscopy, Irvine et al. (2002) showed that labeled mouse class II complexes containing even a single agonist peptide on antigen-presenting cells (APCs) are sufficient to evoke CD4-mediated transient calcium signaling by T cells. Only about 10 agonists are required for the contact zone between a T cell and an APC to form a CD4-dependent immunologic synapse.
Ben-Sasson et al. (2009) reported that Il1-alpha (IL1A; 147760) and Il1-beta (IL1B; 147720), but not other proinflammatory cytokines, markedly induced robust and durable primary and secondary Cd4 responses in mice, with an increase in cells producing Il17 (603149) and Il4 (147780), as well as serum IgG1 and IgE.
Zhou et al. (2007) constructed stabilized HIV-1 gp120 molecules constrained to stay in the CD4-bound conformation, even in the absence of CD4, and determined the crystal structure of gp120 in complex with the neutralizing IgG1 antibody b12 at 2.3-angstrom resolution. Their analyses revealed the functionally conserved surface that allows for initial CD4 attachment and delineated the b12 epitope at the atomic level. Zhou et al. (2007) proposed that the b12 epitope serves as a key target for humoral neutralization of HIV-1 in long-term nonprogressors.
OKT4 Epitope Deficiency
The OKT4 epitope of the CD4 protein is polymorphic in various populations. In African American, Caucasian, and Japanese individuals with OKT4 epitope deficiency (613949), Hodge et al. (1991) identified a C-to-T change at nucleotide 868 of the CD4 gene, resulting in an arg240-to-trp (R240W; 186940.0001) substitution. Independently, Lederman et al. (1991) and Takenaka et al. (1993) identified the R240W substitution as the cause of OKT4 epitope deficiency.
Immunodeficiency 79
In a 45-year-old white woman, born of consanguineous Portuguese parents, with immunodeficiency-79 (IMD79; 619238), Fernandes et al. (2019) identified a homozygous splice site mutation in the CD4 gene (186940.0002). The mutation resulted in the production of truncated proteins with normal extracellular domains in the absence of the anchoring domain to the membrane. The mutation, which was found by direct sequencing of the CD4 gene, segregated with the disorder in the family. Functional studies of the variant were not performed, but CD4 antigen was not expressed on patient T cells, monocytes, or dendritic cells. Soluble CD4 was present in plasma.
In a 22-year-old white woman with IMD79, Lisco et al. (2021) identified a homozygous mutation in the initiation codon of the CD4 gene (186940.0003), preventing mRNA translation and abrogating expression of the entire CD4 protein. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Functional studies were not performed, but there was complete loss of membrane CD4 expression in T cells, monocytes, and various tissue samples. Soluble CD4 was also not detected, consistent with a complete loss of function. Detailed studies showed relative expansion of CD4-/CD8- double-negative T cells that had some characteristics of CD4+ T cells, including expression of regulatory T-cell markers, expression of CD40 ligand upon activation, and expression of cytokines in response to stimulation. Patient CD8+ T cells and double-negative T cells included MHC II-restricted cytomegalovirus (CMV)-specific T cells, illustrating compensatory mechanisms and plasticity of T-cell development in the absence of CD4. There were also secondary B-cell and NK cell abnormalities.
Tishkoff et al. (1996) reported linkage disequilibrium at the CD4 locus on the basis of their studies in 42 geographically dispersed populations. An Alu deletion polymorphism is associated with a short tandem repeat polymorphism (STRP) in non-African and North-East African populations. The Alu deletion is associated with a wide range of STRP alleles in Sub-Saharan African populations. On the basis of this finding the authors proposed a common and recent origin for all non-African human populations. The STRP polymorphism described by Tishkoff et al. (1996) consisted of a pentanucleotide sequence repeated between 4 and 15 times. The Alu deletion polymorphism that they described resulted from a 256-bp deletion of a 285-bp Alu element.
Sawada et al. (1994) and Siu et al. (1994) identified a silencer element in the first intron of the mouse CD4 gene that is sufficient to repress CD4 transcription in cells of the CD8 (186910) lineage, as well as in thymocytes at earlier stages of differentiation. Using mice in which the CD4 silencer can be conditionally deleted, Zou et al. (2001) showed that the functional element is required only at distinct stages of development. If deleted before the initiation of lineage specification, CD4 is derepressed and, therefore, expressed at stages where thymocytes are normally double-negative (CD4-/CD8-). In mutant mice, there are no CD8 single-positive cells in the thymus. Mature thymocytes express either CD4 alone or both CD4 and CD8. Trichostatin A (TSA), an inhibitor of deacetylation, was not able to reactivate the silenced CD4 locus, suggesting that at least TSA-sensitive histone deacetylases (see HDAC3, 605166) are not involved in maintaining CD4 silencing. Zou et al. (2001) concluded that the CD4 silencer is essential for converting a transcriptionally active CD4 locus into a heritably silenced state. The silencer must be maintained in newly committed CD8+ thymocytes to generate an epigenetically silent CD4 locus in mature daughter cells.
Sun and Bevan (2003) found that mice lacking Cd4 mounted a primary Cd8 response equal to that of wildtype mice and rapidly cleared infection with Listeria monocytogenes. However, the Cd4-deficient mice had defective memory Cd8-positive T cells over time, indicating a need for Cd4 help in promoting protective Cd8 memory development. Sun and Bevan (2003) proposed that vaccination schemes targeting only CD8 immunity may fail to provide long-term protection.
Shedlock and Shen (2003) showed that memory Cd8 cells generated in the presence of Cd4 cells responded normally in Cd4 -/- mice, whereas Cd8 cells induced in Cd4 -/- mice were defective in their recall responses to both lymphocytic choriomeningitis virus and L. monocytogenes antigens in Cd4 +/+ mice. They concluded that CD4-positive cells are required in the priming phase for functional CD8 memory, but they are dispensable during the recall response for secondary expansion.
In a mouse model of hindlimb ischemia, Stabile et al. (2003) demonstrated that Cd4 -/- mice had reduced collateral flow induction, macrophage number, and vascular endothelial growth factor (VEGF; 192240) levels in the ischemic muscle, with delayed recovery of hindlimb function and increased muscle atrophy and fibrosis, compared to wildtype mice. Spleen-derived purified Cd4+ T cells infused into Cd4 -/- mice selectively localized to the ischemic limb and significantly increased collateral flow as well as macrophage number and VEGF levels in the ischemic muscle, with improvement in muscle function and damage. Stabile et al. (2003) suggested that CD4+ T cells control the arteriogenic response to acute hindlimb ischemia, at least in part, by recruiting macrophages to the site of active collateral artery formation, which in turn triggers the development of collaterals through the synthesis of arteriogenic cytokines.
Tissues of the nervous system are shielded from plasma proteins, such as antibodies, by the blood-brain and blood-nerve barriers. Iijima and Iwasaki (2016) examined the mechanisms by which circulating antibodies access neuronal tissues in a mouse model of genital herpes (HSV-2) infection. (Converse (2016) noted that others, such as Svensson et al. (2005) (see TBX21, 604895), have explored additional requirements for immune protection against HSV-2.) Iijima and Iwasaki (2016) found that memory Cd4-positive T cells migrated to dorsal root ganglia (DRG) harboring latent HSV-2 and released Ifng (147570), leading to a local increase in vascular permeability that enabled antibody to access the DRG and control the virus. Mice lacking Ifngr1 (107470) were also more susceptible to intravaginal HSV-2 challenge. Depletion of Cd4 cells, but not Cd8 or natural killer cells, rendered mice unable to resist HSV-2 challenge or to respond effectively after intranasal vaccination. Iijima and Iwasaki (2016) concluded that the efficacy of circulating antibody-mediated protection requires CD4 T cells and IFNG.
CD4 is the official designation for T-cell antigen T4/leu3, consistent with the recommendation of the Committee on Human Leukocyte Differentiation Antigens, IUIS WHO Nomenclature Subcommittee (1984). CD stands for 'cluster of differentiation'; the number that follows is arbitrarily assigned. In the full designation the cell type and nature and molecular weight of the antigen are given in brackets; for CD4, this is as follows: [T,gp55].
In African American, Caucasian, and Japanese individuals with OKT4 epitope deficiency (OKT4D; 613949), Hodge et al. (1991) identified a C-to-T change at nucleotide 868 of the CD4 gene, resulting in an arg240-to-trp (R240W) substitution.
Independently, Lederman et al. (1991) identified a G-to-A change at nucleotide 867 of the CD4 gene, resulting in an R240W substitution, in an individual homozygous for OKT4 epitope deficiency. Expression of a CD4 cDNA containing this SNP confirmed that the R240W substitution ablated binding of the OKT4 monoclonal antibody. Lederman et al. (1991) noted that a positively charged amino acid at this position is found in chimpanzee, rhesus macaque, mouse, and rat, suggesting that the R240W change may confer unique functional properties to the OKT4-negative CD4 protein.
Takenaka et al. (1993) identified the R240W substitution in 4 individuals with OKT4 epitope deficiency from a large Japanese family. Analysis showed different hydrophobicity at positions 239 and 240 of OKT-negative CD4 from control, probably giving rise to a conformational change that accounted for the lack of reactivity with OKT4.
In a 45-year-old white woman, born of consanguineous Portuguese parents, with immunodeficiency-79 (IMD79; 619238), Fernandes et al. (2019) identified a homozygous G-to-A transition in the last basepair of intron 7 of the CD4 gene (g.6818420G-A, NC_000012.12) predicted to alter a splice acceptor site. PCR analysis detected 2 truncated CD4 isoforms due to frameshifts and premature termination. The first abnormal transcript had a complete deletion of exon 8 (122 bp, c.1157_1278del, NM_000616), resulting in a truncated 399-residue protein, and the second smaller 29-bp deletion (c.1157_1185del, NM_000616) resulted in production of a truncated 430-residue protein. Both truncated proteins had normal extracellular domains in the absence of the anchoring domain to the membrane. The mutation, which was found by direct sequencing of the CD4 gene, segregated with the disorder in the family. Functional studies of the variant were not performed, but CD4 antigen was not expressed on patient T cells, monocytes, or dendritic cells. Soluble CD4 was present in plasma. The patient had recalcitrant warts since childhood, but did not have a history of recurrent infections.
In a 22-year-old white woman with immunodeficiency-79 (IMD79; 619238), Lisco et al. (2021) identified a homozygous c.1A-G transition (c.1A-G, NM_000616) in the initiation codon of the CD4 gene, preventing mRNA translation and abrogating expression of the entire CD4 protein. The mutation, which was found by direct sequencing, segregated with the disorder in the family. It was present at a low frequency (3.6 x 10(-5)) in the heterozygous state in the gnomAD database. Functional studies were not performed, but there was complete loss of membrane CD4 expression in T cells, monocytes, and various tissue samples. Soluble CD4 was also not detected, consistent with a complete loss of function. The patient had recalcitrant warts since childhood as well as a history of recurrent infections.
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