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 TCRα/β¹(o)CD⁴(int)/CD8(int) (DP (int)) c-Kit⁺ cells to TCRα/β(med) c-Kit⁺ transitional intermediate cells (the c-Kit⁺ pathway). Cells that fail positive selection on the c-Kit⁺ pathway become TCRα/β¹(o)c-Kit^- (DP(hi)) blasts that appear to undergo alternative TCRα rearrangements. The rare DP(hi)c-Kit^- blast cells that thus are salvaged for positive selection by expressing a self-major histocompatibility complex selectable TCRα/β 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 TCR¹(o-med) c-Kit⁺ transition, but is not essential for CD4 lineage maturation from DP(hi) c-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.