title: Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ(+)CD4(-)CD8β(-) intraepithelial lymphocyte lineage.
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.
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: McDonald
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Bunker
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Isabel E
authors.initials: IE
authors.lastname: Ishizuka
authors.affiliation: Committee on Immunology, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Bendelac
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D017637:Clonal Deletion / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D037181:Lectins, C-Type; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000099192:CD69 Antigens; C491383:Pdcd1 protein, mouse