IL-1 uses distinct mechanisms to enhance CD8+ T cell expansion and differentiation.

Abstract

Abstract IL-1 is a potent proinflammatory cytokine with pleiotropic functions within and outside the immune system. We previously showed that IL-1 promotes antigen-specific CD8+ T cell expansion, effector function, and memory differentiation but the underlying mechanisms remain unclear. Here we report that IL-1 likely utilizes distinct pathways to drive CD8 T cell expansion and effector differentiation. Maximal expansion in the peripheral tissues (spleen, lung, and liver) was only achieved when IL-1 acted on both CD8 T cells and non-T cells, which involved cells of hematopoietic and non-hematopoietic origins. Although IL-1did not affect the abundance of CD8 T cells in the draining lymph nodes (dLNs), these IL-1-treated, dLN-derived CD8 T cells expanded more robustly than their control treated counterparts after getting into the tissues. IL-1 treatment also enhanced cytotoxic function, as evidenced by increased granzyme B expression, of CD8 T cells in both dLNs and tissues. This effect was mediated by IL-1R1 signaling in non-hematopoietic cells, especially vascular endothelial cells, but not in CD8 T cells or other hematopoietic cells. Furthermore, CD8 T cells were endowed with a T-bet(hi)Eomes(low) phenotype by IL-1 and did not succumb to apoptosis but rather generated better memory cells both quantitatively and qualitatively than did their control treated counterparts. Collectively, this study demonstrates novel and complex mechanisms used by IL-1 to enhance antigen-specific CD8 T cell responses, which may shed light into developing novel strategies for optimizing CTL responses in treating cancer and infectious diseases.