Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and its mitogenic action

STAT5 proteins are vital for lymphocyte development and function. Cytokine activation of STAT5A and STAT5B involves the tyrosine phosphorylation of a C-terminal tyrosine in each protein; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generated Stat5a and Stat5b tyrosine mutant knockin mice and found they had greatly reduced CD8+ T-cell numbers. Morever, these cells exhibited profoundly diminished IL-2-induced proliferation, correlating with reduced IL-2- mediated induction of Myc, pRB, a range of cyclins and CDKs, and a G1àS phase- transition block. The mutant CD8+ T cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2Rb and IL-2Rg. Our findings demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling, and our transcriptomic and proteomic analyses elucidate the molecular basis for the mitogenic effects of IL-2 on CD8+ T cells.