Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus

T cell antigen receptor (TCR) signaling in the thymus initiates positive selection, but the CD8(+)-lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We have identified four cytokines (IL-6, IFN-gamma, TSLP and TGF-beta) that did not signal via the common gamma-chain (gamma(c)) receptor but that, like IL-7 and IL-15, induced expression of the lineage-specifying transcription factor Runx3d and signaled the generation of CD8(+) T cells. Elimination of in vivo signaling by all six of these 'lineage-specifying cytokines' during positive selection eliminated Runx3d expression and completely abolished the generation of CD8(+) single-positive thymocytes. Thus, this study proves that signaling during positive selection by lineage-specifying cytokines is responsible for all CD8(+)-lineage-fate 'decisions' in the thymus.