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Absence of Innate MyD88 Signaling Promotes Inducible Allograft Acceptance¹

Wendy E. Walker^2,*, Isam W. Nasr^2,*, Geoffrey Camirand^*, Bethany M. Tesar^*, Carmen J. Booth and Daniel R. Goldstein^3,*

^* Department of Internal Medicine, Yale University School of Medicine; and Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520

Prior experimental strategies to induce transplantation tolerance have focused largely on modifying adaptive immunity. However, less is known concerning the role of innate immune signaling in the induction of transplantation tolerance. Using a highly immunogenic murine skin transplant model that resists transplantation tolerance induction when innate immunity is preserved, we show that absence of MyD88, a key innate Toll like receptor signal adaptor, abrogates this resistance and facilitates inducible allograft acceptance. In our model, absence of MyD88 impairs inflammatory dendritic cell responses that reduce T cell activation. This effect increases T cell susceptibility to suppression mediated by CD4⁺CD25⁺ regulatory T cells. Therefore, this study provides evidence that absence of MyD88 promotes inducible allograft acceptance and implies that inhibiting innate immunity may be a potential, clinically relevant strategy to facilitate transplantation 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 was supported by National Institutes of Health Grant AI064660 (to D.R.G.).

² Contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Daniel R. Goldstein, 333 Cedar Street, 3 FMP, P.O. Box 208017, New Haven, CT 06520-8018. E-mail address: daniel.goldstein{at}yale.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; SPC, spleen cell; T reg, regulatory T cell; BMDC, bone marrow-derived DC; MST, median survival time.

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