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TLR Signals Promote IL-6/IL-17-Dependent Transplant Rejection¹

Luqiu Chen^*, Emily Ahmed, Tongmin Wang, Ying Wang^*, Jordi Ochando, Anita S. Chong^2, and Maria-Luisa Alegre^2,3,*

^* Department of Medicine and Department of Surgery, Committee on Immunology, University of Chicago, Chicago, IL 60637; and Inmunología de Trasplantes, Instituto de Salud Carlos III, Madrid, Spain

Acute allograft rejection has often been correlated with Th1 differentiation, whereas transplantation tolerance is frequently associated with induction of regulation. The discovery of the Th17 phenotype has prompted its scrutiny in transplant rejection. Although IL-17 has recently been observed in settings of acute allograft rejection and drives rejection in T-bet-deficient mice that have impaired type 1 T cell responses, there is little evidence of its requirement during acute rejection in wild-type animals. We and others have previously shown that TLR9 signaling by exogenous CpG at the time of transplantation is sufficient to abrogate anti-CD154-mediated acceptance of fully mismatched cardiac allografts. In this study, we investigated the mechanism by which acute rejection occurs in this inflammatory context. Our results indicate that CpG targets recipient hemopoietic cells and that its pro-rejection effects correlate both with prevention of anti-CD154-mediated conversion of conventional CD4⁺ T cells into induced regulatory T cells and with the expression of IFN- and IL-17 by intragraft CD4⁺ T cells. Moreover, the combined elimination of IL-6 and IL-17 signaling abrogated the ability of CpG to promote acute cardiac allograft rejection. Thus, proinflammatory signals at the time of transplantation can change the quality of the effector immune response and reveal a pathogenic function for IL-6 and IL-17 in wild-type recipients.

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 grants from American Heart Association (0620026Z; to L.C.), National Institute of Allergy and Infectious Diseases (NIAID) (R01 AI071080; to M.-L.A.), and NIAID (R01 AI072630; to A.S.C.).

² Cosenior authors.

³ Address correspondence and reprint requests to Dr. Maria-Luisa Alegre, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: malegre{at}midway.uchicago.edu

⁴ Abbreviations used in this paper: iTreg, induced regulatory CD4⁺ T cell; DST, donor-specific transfusion; LN, lymph node; Tg, transgenic.