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A Novel Alloantigen-Specific CD8⁺PD1⁺ Regulatory T Cell Induced by ICOS-B7h Blockade In Vivo¹

Atsushi Izawa^2,*, Kazuhiro Yamaura^2,*, Monica J. Albin^*, Mollie Jurewicz^*, Katsunori Tanaka^*, Michael R. Clarkson^*, Takuya Ueno, Antje Habicht^*, Gordon J. Freeman, Hideo Yagita, Reza Abdi^*, Todd Pearson^¶, Dale L. Greiner^¶, Mohamed H. Sayegh^3,* and Nader Najafian^*

^* Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115; Department of Surgery, Massachusetts General Hospital, Boston, MA 02114; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115; Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and ^¶ Department of Medicine, University of Massachusetts Medical School, Worchester, MA 01655

Delayed ICOS-B7h signal blockade promotes significant prolongation of cardiac allograft survival in wild-type but not in CD8-deficient C57BL/6 recipients of fully MHC-mismatched BALB/c heart allografts, suggesting the possible generation of CD8⁺ regulatory T cells in vivo. We now show that the administration of a blocking anti-ICOS mAb results in the generation of regulatory CD8⁺ T cells. These cells can transfer protection and prolong the survival of donor-specific BALB/c, but not third party C3H, heart grafts in CD8-deficient C57BL/6 recipients. This is unique to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice and does not result in the generation of regulatory CD8⁺ T cells. Those cells localize to the graft, produce both IFN- and IL-4 after allostimulation in vitro, prohibit the expansion of alloreactive CD4⁺ T cells, and appear to mediate a Th2 switch of recipient CD4⁺ T cells after adoptive transfer in vivo. Finally, these cells are not confined to the CD28-negative population but express programmed death 1, a molecule required for their regulatory function in vivo. CD8⁺PD1⁺ T cells suppress alloreactive CD4⁺ T cells but do not inhibit the functions by alloreactive CD8⁺ T cells in vitro. These results describe a novel allospecific regulatory CD8⁺PD1⁺ T cell induced by ICOS-B7h blockade in vivo.

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 Institute of Health Grants R01 AI51559, P01 AI041521, and P01 AI56299. N.N. is a recipient of the American Society of Transplantation Faculty Grant, the American Society of Nephrology John Merrill Transplant Scholar Grant, and the American Heart Association Scientist Development Grant.

² A.I. and K.Y. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Mohamed H. Sayegh, Brigham and Women’s Hospital, Transplantation Research Center, EBRC, 221 Longwood Avenue, Third Floor, Boston, MA 02115. E-mail address: msayegh{at}rics.bwh harvard.edu

⁴ Abbreviations used in this paper: B6, C57BL/6; PD-1, programmed death 1; CD8icos, CD8⁺ T cells derived from animals tested with anti-ICOS mAb; CD8iso, CD8⁺ T cells derived from animals tested with isotype control Ig; GITR, glucocorticoid-induced TNF receptor; PD-L, PD ligand; hpf, high power field; MST, median survival time; WT, wild type.

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