Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP expression (46.4)

Abstract

Abstract The nature of inflammatory signals determines the outcome of T cell responses. However, little is known about how inflammatory cytokines provided to human CD8 T cells during activation affect their susceptibility to post-activation cell death. We have examined and compared the effects of the inflammatory cytokines IL-12, as well as the combination of IL-1, IL-6, and IL-23 (IL-1/6/23) on the susceptibility of primary human CD8 T cells to post-activation cell death. Human CD8 T cells activated in the presence of IL-1/6/23 underwent significantly less cell death after activation as compared to those activated in IL-12. This was due to reduced susceptibility to Fas-mediated activation-induced cell death (AICD). CD8 T cells activated in IL-1/6/23 expressed less FasL and more c-FLIPs as compared to those activated in IL-12, and were also less sensitive to cell death induced by a Fas agonistic antibody. Inhibition of c-FLIP expression by siRNA increased cell death of CD8 T cells activated in both conditions. When the effect of IL-1, IL-6, and IL-23 individually was examined, IL-1 or IL-6 alone was sufficient to inhibit CD8 T cell death that occurs after activation in IL-12 while the effect of IL-23 was variable. Our findings show that the presence of IL-1 and/or IL-6 during activation of human CD8 T cells attenuates Fas-mediated AICD while IL-12 increases the susceptibility of activated CD8 T cells to this form of cell death.