Intrinsic IL-21 signaling is critical for CD8 T cell memory formation in response to Vaccinia viral infection (50.32)

Abstract

Abstract The role of CD4 T cell help in primary and memory CD8 T cell responses to infectious pathogens remains incompletely defined. We showed previously that CD4 help provided during both the primary and secondary responses to vaccinia virus (VV) is required for the survival of activated CD8 T cells. Still unclear however, is the mechanism of CD4 help during the response to VV infection. Here we demonstrate that CD4 help is neither dependent on dendritic cell (DC) priming nor is contact dependent, indicating that CD4 help may be dependent on a soluble mediator. We determined that in vitro CD4 help for CD8 survival is dependent on IL-21, a cytokine produced predominantly by activated CD4 T cells. Furthermore, IL-21 signaling is required for the survival of activated CD8 T cells in vivo and CD8 T cells deficient in IL-21 signaling failed to develop a memory pool. In addition, we observed that IL-21 signaling in CD8 T cells can activate the STAT1 and STAT3 signaling pathways, both of which have been correlated to CD8 survival. Our study shows that direct IL-21 signaling is required for the formation of memory CD8 cells in response to VV and indicates that CD4-help may be mediated by IL-21 during VV infection. This suggests that differential IL-21 requirements during different pathogen infections may dictate the necessity of CD4 help in the primary CD8 response.