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 TCR alpha/beta(lo)CD4(int)/CD8(int) (DPint) c-Kit(+) cells to TCR alpha/beta(med)c-Kit(+) transitional intermediate cells (the c-Kit(+) pathway). Cells that fail positive selection on the c-Kit(+) pathway become TCR alpha/beta(lo)c-Kit(-) (DPhi) blasts that appear to undergo alternative TCR alpha rearrangements. The rare DP(hi)c-Kit(-) blast cells that thus are salvaged for positive selection by expressing a self-major histocompatibility complex selectable TCR alpha/beta upregulate 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 TCR(lo.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.