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 affects their susceptibility to post-activation cell death. We have examined and compared the effects of the inflammatory cytokine 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 with those activated in IL-12. This was due to reduced susceptibility to Fas-mediated activation-induced cell death (AICD). Mechanistically, the reduced level of cell death in CD8 T cells activated in IL-1/6/23 was a result of a low level of FasL expression and high level of c-FLIP(S) expression. 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. IL-1, but not IL-6, inhibited expression of FasL, whereas IL-6, but not IL-1, increased c-FLIP(S) expression. Our findings show that the presence of IL-1 and/or IL-6 during activation of human CD8 T cells attenuates Fas-mediated AICD, whereas IL-12 increases the susceptibility of activated CD8 T cells to this form of cell death.
Highlights
JUNE 17, 2011 VOLUME 286 NUMBER 24 of caspase-8 followed by the activation of caspase-3, which leads to dismantling of the cell
Human CD8 T Cells Activated in IL-1/6/23 Undergo Less activation-induced cell death (AICD) Than Those Activated in IL-12—To begin examining the effects of inflammatory cytokines on CD8 T cell death, primary
In co-cultures of CD8 T cells receiving cellular FLICE inhibitory protein (c-FLIP) siRNA, there was no difference in cell death of cells that had been activated in IL-1/6/23 as compared with IL-12 (Fig. 5D). These findings indicate that the higher level of c-FLIPS expression in human CD8 T cells activated in IL-1/6/23 accounts for the intrinsic resistance of these cells to Fas-mediated AICD but that lower levels of FasL expression dictated by IL-1/6/23 can result in less induction of Fas-mediated cell death
Summary
JUNE 17, 2011 VOLUME 286 NUMBER 24 of caspase-8 followed by the activation of caspase-3, which leads to dismantling of the cell. We examine the effects of inflammatory cytokines on determining the susceptibility of human CD8 T cells to post-activation cell death.
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