Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ(+)CD4(-)CD8β(-) intraepithelial lymphocyte lineage

Benjamin D McDonald; Jeffrey J Bunker; Isabel E Ishizuka; Bana Jabri; Albert Bendelac

doi:10.1016/j.immuni.2014.07.008

Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ(+)CD4(-)CD8β(-) intraepithelial lymphocyte lineage

Immunity. 2014 Aug 21;41(2):219-29. doi: 10.1016/j.immuni.2014.07.008. Epub 2014 Aug 14.

Authors

Benjamin D McDonald¹, Jeffrey J Bunker¹, Isabel E Ishizuka¹, Bana Jabri², Albert Bendelac³

Affiliations

¹ Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
² Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
³ Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA. Electronic address: abendela@bsd.uchicago.edu.

Abstract

The origin and developmental pathway of intestinal T cell receptor αβ(+) CD4(-)CD8β(-) intraepithelial lymphocytes (unconventional iIELs), a major population of innate-like resident cytolytic T cells, have remained elusive. By cloning and expressing several TCRs isolated from unconventional iIELs, we identified immature CD4(lo)CD8(lo)(DP(lo))CD69(hi)PD-1(hi) thymocytes as the earliest postsignaling precursors for these cells. Although these precursors displayed multiple signs of elevated TCR signaling, a sizeable fraction of them escaped deletion to selectively engage in unconventional iIEL differentiation. Conversely, TCRs cloned from DP(lo)CD69(hi)PD-1(hi) thymocytes, a population enriched in autoreactive thymocytes, selectively gave rise to unconventional iIELs upon transgenic expression. Thus, the unconventional iIEL precursor overlaps with the DP(lo) population undergoing negative selection, indicating that, concomitant with the downregulation of both CD4 and CD8 coreceptors, a balance between apoptosis and survival signals results in outcomes as divergent as clonal deletion and differentiation to the unconventional iIEL lineage.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / biosynthesis
Antigens, CD / genetics
Antigens, CD / immunology
Antigens, Differentiation, T-Lymphocyte / biosynthesis
Antigens, Differentiation, T-Lymphocyte / genetics
Antigens, Differentiation, T-Lymphocyte / immunology
Apoptosis / immunology
CD4-Positive T-Lymphocytes / cytology*
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / cytology*
CD8-Positive T-Lymphocytes / immunology
Cell Differentiation / immunology*
Cell Lineage / immunology
Cells, Cultured
Clonal Deletion / immunology
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class II / immunology
Lectins, C-Type / biosynthesis
Lectins, C-Type / genetics
Lectins, C-Type / immunology
Mice
Mice, Transgenic
Programmed Cell Death 1 Receptor / biosynthesis
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Receptors, Antigen, T-Cell, alpha-beta / immunology*
Signal Transduction / immunology

Substances

Antigens, CD
Antigens, Differentiation, T-Lymphocyte
CD69 antigen
Histocompatibility Antigens Class I
Histocompatibility Antigens Class II
Lectins, C-Type
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell, alpha-beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding