Abstract
Interleukin (IL)-4 is a cytokine classically associated with CD4(+) T helper type 2 differentiation, but has been recently shown to also be required for the development of CD8(+) innate-like lymphocytes. CD8(+) innate-like lymphocytes are non-conventional lymphocytes that exhibit characteristics typically associated with memory CD8(+) T cells, including expression of the T-box transcription factor Eomesodermin (Eomes). Here we investigate the signaling pathways required for IL-4 induction of Eomes and CD8(+) innate-like lymphocyte markers in murine CD8SP thymocytes and peripheral CD8(+) T cells. We demonstrate that IL-4 is sufficient to drive Eomes expression and the CD8(+) innate-like lymphocyte phenotype through cooperation between STAT6- and Akt-dependent pathways. Furthermore, we show that while IL-4 has little effect on the induction of Eomes in the setting of robust T cell receptor (TCR) activation, this cytokine promotes Eomes in the setting of attenuated TCR stimulation in mature CD8(+) T cells suggesting that cytokine signaling pathways may direct cell fate when TCR signals are limiting.