Two distinct pathways of positive selection for thymocytes.
Most mouse thymocytes undergoing positive selection are found on one of two pathways; the c-Kit+ and the c-Kit- pathways. Here, we show that c-Kit and interleukin-7 receptor (IL-7R)-mediated signals support positive selection during the transition from the subpopulation that first expresses cell surface T cell receptor (TCR)-the TCRalpha/betaloCD4(int)/CD8(int) (DPint) c-Kit+ cells to TCRalpha/betamedc-Kit+ transitional intermediate cells (the c-Kit+ pathway). Cells that fail positive selection on the c-Kit+ pathway become TCRalpha/betaloc-Kit- (DPhi) blasts that appear to undergo alternative TCRalpha rearrangements. The rare DPhic-Kit- blast cells that thus are salvaged for positive selection by expressing a self-major histocompatibility complex selectable TCRalpha/beta up-regulate IL-7R, but not c-Kit, and are the principal progenitors on the c-Kit- pathway; this c-Kit-IL-7R+ pathway is mainly CD4 lineage committed. Cell division is a feature of the TCRlo-medc-Kit+ transition, but is not essential for CD4 lineage maturation from DPhic-Kit- blasts. In this view, positive selection on the c-Kit- path results from a salvage of cells that failed positive selection on the c-Kit+ path.
Akashi
K
K
Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Akashi@Darwin.Stanford.edu
Kondo
M
M
Weissman
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IL
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D005434:Flow Cytometry; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006239:Haplotypes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D018123:Receptors, Interleukin / Q000096:biosynthesis; D020395:Receptors, Interleukin-7; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics
D015703:Antigens, CD; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D001613:beta 2-Microglobulin; D019009:Proto-Oncogene Proteins c-kit