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Type 1 IFN Mediates Cross-Talk between Innate and Adaptive Immunity That Abrogates Transplantation Tolerance^1,2

Thomas B. Thornley^*, Nancy E. Phillips^*, Britte C. Beaudette-Zlatanova^*, Thomas G. Markees^*, Kapil Bahl, Michael A. Brehm, Leonard D. Shultz, Evelyn A. Kurt-Jones, John P. Mordes^*, Raymond M. Welsh, Aldo A. Rossini^* and Dale L. Greiner^3,*

^* Department of Medicine, Division of Diabetes, Department of Pathology, and Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and The Jackson Laboratory, Bar Harbor, ME 04609

TLR activation of innate immunity prevents the induction of transplantation tolerance and shortens skin allograft survival in mice treated with costimulation blockade. The mechanism by which TLR signaling mediates this effect has not been clear. We now report that administration of the TLR agonists LPS (TLR4) or polyinosinic:polycytidylic acid (TLR3) to mice treated with costimulation blockade prevents alloreactive CD8⁺ T cell deletion, primes alloreactive CTLs, and shortens allograft survival. The TLR4- and MyD88-dependent pathways are required for LPS to shorten allograft survival, whereas polyinosinic:polycytidylic acid mediates its effects through a TLR3-independent pathway. These effects are all mediated by signaling through the type 1 IFN (IFN-β) receptor. Administration of IFN-β recapitulates the detrimental effects of TLR agonists on transplantation tolerance. We conclude that the type 1 IFN generated as part of an innate immune response to TLR activation can in turn activate adaptive immune responses that abrogate transplantation tolerance. Blocking of type 1 IFN-dependent pathways in patients may improve allograft survival in the presence of exogenous TLR ligands.

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 National Institutes of Health Grants AI46629, DK53006, AI17672, and AI51405; institutional Diabetes Endocrinology Research Center Grant DK32520; Juvenile Diabetes Foundation; and International Grants 1-2002-396 and 1-2004-548.

² The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Dale L. Greiner, Diabetes Division, University of Massachusetts Medical School, Two Biotech, 373 Plantation Street, Suite 218, Worcester, MA 01605. E-mail address: dale.greiner{at}umassmed.edu

⁴ Abbreviations used in this paper: DST, donor-specific transfusion; IFN-RI, type I IFN receptor; MST, median survival time; poly(I:C), polyinosinic:polycytidylic acid; KU, kilounit; DES, Desiré mAb.

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