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Natural Regulation of Immunity to Minor Histocompatibility Antigens¹

Nathan J. Robertson^*, Jian-Guo Chai^*, Maggie Millrain^*, Diane Scott^*, Fazila Hashim^*, Emily Manktelow, François Lemonnier, Elizabeth Simpson^* and Julian Dyson^2,*

^* Transplantation Biology Group, Department of Immunology, Imperial College London, Hammersmith Hospital, London, United Kingdom; Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and Antiviral Cell Immunology, Institute Pasteur, Paris, France

MHC-matched hemopoietic stem cell transplantation is commonly used for the treatment of some forms of leukemia. Conditioning regimens before transplant act to reduce the burden of leukemic cells and the graft-vs-leukemia (GvL) effect can eliminate residual disease. The GvL effect results largely from the recognition of minor histocompatibility Ags by donor T cells on recipient tissues. These Ags are generally widely expressed and also provoke graft-vs-host (GvH) disease. Manipulation of immunity to promote GvL while curtailing GvH would greatly improve clinical outcome. To develop strategies that may achieve this, the parameters which control immunity to minor histocompatibility Ags need to be defined. In this study, we have analyzed responses to the mouse HY minor histocompatibility Ag using hemopoietic cell and skin grafts as surrogate GvL and GvH targets, respectively. We show that natural regulation of CD8 T cell responses to HY operates at multiple levels. First, CD4 T cell help is required for primary CD8 responses directed at hemopoietic cells. However, although CD4 T cells of H2^k mouse strains recognize HY, they provide ineffective help associated with a proportion of recipients developing tolerance. This was further investigated using TCR-transgenic mice which revealed H2^k-restricted HY-specific CD4 T cells are highly susceptible to regulation by CD25⁺ regulatory T cells which expand in tolerant recipients. A second level of regulation, operating in the context of skin grafts, involves direct inhibition of CD8 T cell responses by CD94/NKG2 engagement of the nonclassical MHC class I molecule Qa1.

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 funded by the U.K. Medical Research Council.

² Address correspondence and reprint requests to Dr. Julian Dyson, Transplantation Biology Group, Department of Immunology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, U.K. E-mail address: peter.dyson{at}imperial.ac.uk

³ Abbreviations used in this paper: GvH, graft-vs-host; Treg, regulatory T cell; ₂m, ₂-microglobulin; KO, knockout; WT, wild type.

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