title: CD8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice.
abstract: 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.
authors.affiliation: Section of General Surgery, Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Bryna E
authors.initials: BE
authors.lastname: Burrell
authors.forename: Keri
authors.initials: K
authors.lastname: Csencsits
authors.forename: Guanyi
authors.initials: G
authors.lastname: Lu
authors.forename: Svetlana
authors.initials: S
authors.lastname: Grabauskiene
authors.forename: D Keith
authors.initials: DK
authors.lastname: Bishop