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• W2327897531 abstract "Introduction: IL-17-producing CD4+ and CD8+ T cells (T17) may play a major role in the pathogenesis of allograft rejection and resistance to tolerance induction. This speculation is based on the observation that T17 cells in T-bet-deficient mice (thus lacking Th1) mediate an aggressive pro-inflammatory alloimmune response resulting in accelerated allograft rejection. However, the basic mechanisms underlying T17-mediated alloimmune responses in transplantation are poorly understood, particularly downstream of the key T17 effector cytokine IL-17 and with respect to regulation by the hallmark T17 transcription factor ROR-gamma-t (RORγt). Methods: To precisely explore the role of RORγt in T17 alloimmunity in the absence of Th1, we created RORγt reporter and knockout mice on a T-bet-deficient (T-bet−/−) background by crossbreeding B6.T-bet−/− with B6. Rorγtgfp/wt reporter and B6. Rorγtgfp/gfp knockout (KO) mice, respectively. CD4+ and CD8+ T effector cells from these mice were studied in T17 conversion assays in vitro and in a heterotopic heart transplant (HTx) model of acute allograft rejection in vivo. Results: First, we explored the fate-mapping capacity of our reporter model by polarizing CD4+ and CD8+ T cells from Rorγtgfp/wtT-bet−/− mice towards T17 and measuring GFP and IL-17 expression in vitro. We discovered that the T17 cells from these mice expressed high levels of GFP and were as capable of producing IL-17 as controls, thus demonstrating the efficacy of our reporter model. Next, we tested whether RORγt significantly contributes to the differentiation of alloreactive T17 cells in the absence of Th1 by studying T cells from Rorγt-T-bet double-KO mice under T17-polarizing conditions in vitro. Importantly, IL-17 expression was substantially lower but still present in the double-KO mice when compared to controls, indicating that RORγt plays an important, but not exclusive, role in driving IL-17-producing T cells in the absence of T-bet. Next, we directly addressed the role of RORγt in T17-mediated alloimmunity in the absence of Th1 in vivo by adoptively transferring FACS-sorted CD3+ T cells from Rorγtgfp/wtT-bet−/− reporter or double-KO mice into B6. Rag−/− recipients of fully mismatched Balb/c HTx. We found that recipients with T cells from Rorγtgfp/wt or Rorγtgfp/gfp controls failed to acutely reject their allografts with the majority surviving long term (50% and 63%, respectively). Surprisingly, however, all recipients transferred with Rorγtgfp/wtT-bet−/− reporter or double-KO T cells promptly rejected their allografts alike recipients transferred with T cells from T-bet−/− controls (MST 21d, 22d, and 18d, respectively), indicating that RORγt seems to be sufficient but not necessary for driving acute allograft rejection in the absence of Th1. Conclusion: In conclusion, RORγt may play a critical but redundant role in T17-mediated alloimmunity. In transplantation, our studies point to an important and as yet understudied role of distinct ROR-transcription factors." @default.
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• W2327897531 date "2012-11-01" @default.
• W2327897531 modified "2023-09-27" @default.
• W2327897531 title "Mechanisms Underlying T17-Mediated Allograft Rejection" @default.
• W2327897531 doi "https://doi.org/10.1097/00007890-201211271-00850" @default.
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