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A Key Role for TGF- Signaling to T Cells in the Long-Term Acceptance of Allografts¹

Therapeutic Immunology Group, Sir William Dunn School of Pathology, Oxford, United Kingdom

TGF- is a key immunoregulatory cytokine which supports self-tolerance by signaling to T cells. In this report, we show a crucial role for TGF- signaling to T cells in enabling the long-term acceptance of allografts, whether natural or induced therapeutically by coreceptor and costimulation blockade. The requirement for TGF- appears most pronounced during the initial exposure to alloantigens. We demonstrate the ability of TGF- to direct the development in vitro of regulatory cells that suppress graft rejection in vivo. Such suppression was not affected by anti-TGF- treatment of the recipient mice. Despite this, TGF- may still have a role in CD4⁺ cell-mediated suppression of antiallograft responses in vivo, since its neutralization can, in some cases, abrogate suppression. These results show that TGF- signaling to T cells is dispensable for mounting destructive responses against skin allografts while appearing to be an essential intermediary in establishing long-term tolerance.

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 supported by a Medical Research Council U.K. Program Grant "Therapeutic Immunoregulation" and the European Union FP6 "RISET" Consortium. S.D. was supported by the Rhodes Trust.

² Current address: John Curtin School of Medical Research, Building 54, ANU, Mills Road, Acton, Australia.

³ S.C. and H.W. contributed equally as joint senior authors.

⁴ Address correspondence and reprint requests to Prof. Herman Waldmann, Sir William Dunn School of Pathology, South Parks Road, Oxford, U.K. E-mail address: herman.waldmann{at}path.ox.ac.uk

⁵ Abbreviations used in this paper: Tgfbr2, TGF- receptor type II; dnTgfbr2, dominant-negative TGF- receptor type II; Treg, regulatory T cell.

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