CD25 signaling via STAT5 is necessary for development of cytolytic CD4 T cells (163.13)

Abstract

Abstract Cytolytic CD4 cells have been identified in vivo during viral infections; however, the factors necessary for driving the cytolytic phenotype have not been characterized. Previously, we found that IL-2 is necessary and sufficient to drive the in vitro differentiation of naïve CD4 cells into cytolytic effectors. To further dissect the role of IL-2 in CD4 CTL generation, TCR transgenic mice deficient in IL-2 production or IL-2Rα (CD25) were used. In vitro, CD25 deficient cells do not express granzyme B (GrB) or acquire cytolytic activity when cultured in the presence of IL-2. In contrast, CD25+/- cells exhibit half maximal expression of GrB and reduced cytotoxicity when compared to WT cells. In vitro, IL-2 activates STAT5 phosphorylation, peaking at 18-24 h, correlating with GrB expression and cytotoxicity by 72-96 h. Inhibition of the JAK3/STAT5 pathway resulted in a dose dependent reduction of GrB expression. Surprisingly, other common γc cytokines such as IL-7 and IL-15 induce STAT5 phosphorylation but do not induce cytotoxicity, most likely due to the timing of STAT5 activation. Studies determining whether STAT5 activation synergizes with other signaling pathways to induce optimal CTL activity are underway. Further, the role of CD25 signaling in the induction of cytolytic activity in vivo during influenza infection will be discussed. These data have implications in the design of vaccines and in adoptive immunotherapy against certain tumors.