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.