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TLR Agonists Prevent the Establishment of Allogeneic Hematopoietic Chimerism in Mice Treated with Costimulation Blockade^1,2

David M. Miller^*, Thomas B. Thornley^*, Todd Pearson^*, Annie J. Kruger^*, Masahiro Yamazaki^*, Leonard D. Shultz^¶, Raymond M. Welsh^,, Michael A. Brehm, Aldo A. Rossini^*,, and Dale L. Greiner^3,*,

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

Activation of TLR4 by administration of LPS shortens the survival of skin allografts in mice treated with costimulation blockade through a CD8 T cell-dependent, MyD88-dependent, and type I IFN receptor-dependent pathway. The effect of TLR activation on the establishment of allogeneic hematopoietic chimerism in mice treated with costimulation blockade is not known. Using a costimulation blockade protocol based on a donor-specific transfusion (DST) and a short course of anti-CD154 mAb, we show that LPS administration at the time of DST matures host alloantigen-presenting dendritic cells, prevents the establishment of mixed allogeneic hematopoietic chimerism, and shortens survival of donor-specific skin allografts. LPS mediates its effects via a mechanism that involves both CD4⁺ and CD8⁺ T cells and results from signaling through either the MyD88 or the type I IFN receptor pathways. We also document that timing of LPS administration is critical, as injection of LPS 24 h before treatment with DST and anti-CD154 mAb does not prevent hematopoietic engraftment but administration the day after bone marrow transplantation does. We conclude that TLR4 activation prevents the induction of mixed allogeneic hematopoietic chimerism through type I IFN receptor and MyD88-dependent signaling, which leads to the up-regulation of costimulatory molecules on host APCs and the generation of alloreactive T cells. These data suggest that distinct but overlapping cellular and molecular mechanisms control the ability of TLR agonists to block tolerance induction to hematopoietic and skin allografts in mice treated with costimulation blockade.

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 in part by National Institutes of Health Research Grant AI42669, American Diabetes Association Grant 7-05-PST-02, the Juvenile Diabetes Research Foundation, International, and Diabetes Endocrinology Center Research Grant DK32520 from the National Institutes of Health.

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, University of Massachusetts Medical School, 373 Plantation Street, Biotech 2, Suite 218, Worcester, MA 01605. E-mail address: dale.greiner{at}umassmed.edu

⁴ Abbreviations used in this paper: DST, donor-specific transfusion; DC, dendritic cell; MFI, median fluorescence intensity; poly(I:C), polyinosinic: polycytidylic acid; Pam3Cys, Pam3-Cys-Ser-(Lys)4; TIRAP, Toll/IL-1 receptor domain-containing adaptor protein; TRAM, TRIF-related adaptor molecule; Treg, regulatory T cell; TRIF, TIR-domain-containing adaptor protein inducing IFN-β; MST, median survival time.