title: Inflammatory cytokines determine the susceptibility of human CD8 T cells to Fas-mediated activation-induced cell death through modulation of FasL and c-FLIP(S) expression.
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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A1S6.
authors.forename: Anna
authors.initials: A
authors.lastname: von Rossum
authors.forename: Randall
authors.initials: R
authors.lastname: Krall
authors.forename: Nichole K
authors.initials: NK
authors.lastname: Escalante
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Choy
mesh_terms: D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D016923:Cell Death; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007375:Interleukin-1; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D018664:Interleukin-12