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 CD8 lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We now identify four non-common gamma chain (γc) receptor-signaling cytokines (IL-6, IFN-γ, TSLP, TGF-β) that, like IL-7 and IL-15, induce expression of the lineage-specifying transcription factor Runx3d and signal the generation of CD8 T cells. Remarkably, elimination of in vivo signaling by all ‘lineage-specifying cytokines’ during positive selection eliminated Runx3d expression and completely abrogated CD8 single-positive thymocyte generation. Thus, this study proves that signaling during positive selection by lineage-specifying cytokines is responsible for all CD8 lineage fate decisions in the thymus.