Signaling by intrathymic cytokines, not T cell receptors, specifies CD8- lineage choice and promotes differentiation of cytotoxic-lineage T cells

Immature CD4CD8 (DP) thymocytes are signaled by their T-cell receptors (TCR) to undergo positive selection into mature CD4+ or CD8+ T cells. TCR signaling converts cytokine-unresponsive DP into cytokine-responsive thymocytes, and we now report that it is subsequent signaling by intrathymic cytokines such as interleukin-7 (IL-7) that induces Runx3 expression, specifies CD8-lineage choice, and promotes cytotoxic- lineage cell differentiation. For DP thymocytes genetically engineered to be cytokine- responsive, IL-7 signaling induced TCR-unsignaled DP thymocytes to express Runx3 and to differentiate into phenotypically mature CD8+ T cells, circumventing positive selection. Thus, TCR-mediated positive selection signaling converts DP thymocytes into cytokine-responsive cells, but it is subsequent signaling by intrathymic cytokines that specifies CD8-lineage choice and promotes differentiation of cytotoxic-lineage T cells.