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CD8⁺ Th17 Mediate Costimulation Blockade-Resistant Allograft Rejection in T-bet-Deficient Mice¹

Bryna E. Burrell^2,*,, Keri Csencsits^2,*, Guanyi Lu^*, Svetlana Grabauskiene^* and D. Keith Bishop^3,*,

^* Section of General Surgery, Department of Surgery, and Graduate Program in Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109

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- 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-^–/– allograft recipients did not induce Th17, suggesting that T-bet, rather than IL-4 and IFN- (known inhibitors of Th17), plays a critical role in negatively regulating Th17 in the transplant setting.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by R01 AI061469 (to D.K.B.) and R01 HL070613 (to D.K.B.) from the National Institutes of Health and the Herman and Dorothy Miller Fund Award for Innovative Immunology Research (to B.E.B.).

² B.E.B. and K.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. D. Keith Bishop, Transplant Immunology Research Laboratory, Section of General Surgery, A560 MSRB II, Box 0654, University of Michigan Medical Center, Ann Arbor, MI 48109. E-mail address: kbishop{at}umich.edu

⁴ Abbreviations used in this paper: WT, wild type; EAE, experimental autoimmune encephalomyelitis; EAM, experimental autoimmune myocarditis; GIC, graft-infiltrating cell.

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