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/β(lo)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/β(lo)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 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.