Resistance of Th17 cells to Activation-Induced Cell Death (47.13)

Abstract

Abstract Peripheral T cells undergo apoptosis induced by repeated TCR stimulation, known as activation-induced cell death (ACID), which plays an important role in T-cell tolerance. AICD in CD4 T helper (Th) cells including Th1 and Th2 effectors has been extensively studied. Recently, IL-17-producing CD4+ T cells (Th17 cells) have been identified as a unique Th subset, but the susceptibility and underneath molecular mechanism of AICD in Th17 effectors have not been defined. In this study, we found that Th17 cells were significantly less susceptible to AICD upon TCR restimulation compared to Th1 cells. The resistance was confirmed on pure Th17 cells by gating on CD4+RFP+ cells that were polarized from CD4 naïve T cells from il17f/rfp knock-in mice. Furthermore, the resistance of Th17 cells to AICD was also observed when Th17 cells were co-cultured in vitro or co-injected in vivo with Th1 cells. To explore the molecular mechanism, we found that Th17 cells were defective in FasL expression and in caspase activation, but highly expressed anti-apoptotic protein c-FLIP. After knocking down c-FLIP with its specific siRNA, Th17 cells re-expressed FasL and underwent rapid apoptosis upon TCR restimulation. In conclusion, Th17 cells are resistant to AICD likely because the high level of c-FLIP prevents Fas-mediated apoptosis. The resistance of Th17 cells to AICD reveals additional mechanism to explain the high pathogenicity of Th17 cells in autoimmune diseases, and may also provide a rationale to generate tumor-specific Th17 cells for adoptive cell immunotherapy.