HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fehr, T. Articles by Sykes, M. Search for Related Content PubMed PubMed Citation Articles by Fehr, T. Articles by Sykes, M.

Alloreactive CD8 T Cell Tolerance Requires Recipient B Cells, Dendritic Cells, and MHC Class II¹

Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129

Allogeneic bone marrow chimerism induces robust systemic tolerance to donor alloantigens. Achievement of chimerism requires avoidance of marrow rejection by pre-existing CD4 and CD8 T cells, either of which can reject fully MHC-mismatched marrow. Both barriers are overcome with a minimal regimen involving anti-CD154 and low dose (3 Gy) total body irradiation, allowing achievement of mixed chimerism and tolerance in mice. CD4 cells are required to prevent marrow rejection by CD8 cells via a novel pathway, wherein recipient CD4 cells interacting with recipient class II MHC tolerize directly alloreactive CD8 cells. We demonstrate a critical role for recipient MHC class II, B cells, and dendritic cells in a pathway culminating in deletional tolerance of peripheral alloreactive CD8 cells.

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 R01 HL49915 and P01 HL18646. T.F. was supported by the Swiss Foundation for Medical and Biological Grants/Novartis Switzerland and the Walter and Gertrud Siegenthaler Foundation (University of Zurich). F.H. was supported by the Fondation pour la Recherche Medicale, France and the American Society of Transplantation/American Society of Blood and Marrow Transplantation.

² T.F. and F.H. contributed equally and are listed alphabetically.

³ Current address: Clinic of Nephrology, University Hospital/Zurich Medical School, Zurich, Switzerland.

⁴ Address correspondence and reprint requests to Dr. Megan Sykes, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East, Building 149-5102, 13th Street, Boston, MA 02129. E-mail address: megan.sykes{at}tbrc.mgh.harvard.edu

⁵ Abbreviations used in this paper: TBI, total body irradiation; BM, bone marrow; BMT, BM transplantation; Treg, regulatory T cell; DC, dendritic cell; DT, diphtheria toxin; DTR, DT receptor; FCM, flow cytometric; WT, wild type; CML, cell-mediated lympholysis; WBC, white blood cell.

This article has been cited by other articles:

				J. Kurtz, F. Raval, C. Vallot, J. Der, and M. Sykes CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance Blood, April 9, 2009; 113(15): 3475 - 3484. [Abstract] [Full Text] [PDF]

				A. Boni, P. Muranski, L. Cassard, C. Wrzesinski, C. M. Paulos, D. C. Palmer, L. Gattinoni, C. S. Hinrichs, C.-C. Chan, S. A. Rosenberg, et al. Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers Blood, December 1, 2008; 112(12): 4746 - 4754. [Abstract] [Full Text] [PDF]

				F. Haspot, T. Fehr, C. Gibbons, G. Zhao, T. Hogan, T. Honjo, G. J. Freeman, and M. Sykes Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway Blood, September 1, 2008; 112(5): 2149 - 2155. [Abstract] [Full Text] [PDF]