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J Immunol. 2008 Sep 15;181(6):3906-14.

CD8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice.

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Section of General Surgery, Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.


While studying Th responses induced by cardiac transplantation, we observed that mice deficient in the Th1 transcription factor T-bet (T-bet(-/-)) mount both Th1 and Th17 responses, whereas wild-type recipients mount only Th1 responses. Cells producing both IFN-gamma and IL-17 were readily detectable within the rejecting graft of T-bet(-/-) recipients, but were absent from the spleen, indicating that the in vivo microenvironment influences Th function. In addition, disrupting CD40-CD40L costimulatory interactions was highly effective at prolonging allograft survival in WT mice, but ineffective in T-bet(-/-) recipients. In this study, we report that CD8(+) Th17 mediate costimulation blockade-resistant rejection in T-bet(-/-) allograft recipients. Depleting CD8(+) cells or neutralizing IL-17 or the Th17-inducing cytokine IL-6 ablated the Th17 response and reversed costimulation blockade-resistant graft rejection. Neutralizing IL-4 in IFN-gamma(-/-) allograft recipients did not induce Th17, suggesting that T-bet, rather than IL-4 and IFN-gamma (known inhibitors of Th17), plays a critical role in negatively regulating Th17 in the transplant setting.

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