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Xenogeneic ₂-Microglobulin Substitution Affects Functional Binding of MHC Class I Molecules by CD8⁺ T Cells¹

Loralyn A. Benoit^* and Rusung Tan^2,

^* Department of Immunology, University of Toronto, Toronto, Ontario, Canada; and Department of Pathology and Laboratory Medicine, British Columbia’s Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada

NK cells and CD8⁺ T cells bind MHC-I molecules using distinct topological interactions. Specifically, murine NK inhibitory receptors bind MHC-I molecules at both the MHC-I H chain regions and ₂-microglobulin (₂m) while TCR engages MHC-I molecules at a region defined solely by the class I H chain and bound peptide. As such, alterations in ₂m are not predicted to influence functional recognition of MHC-I by TCR. We have tested this hypothesis by assessing the capability of xenogeneic ₂m to modify the interaction between TCR and MHC-I. Using a human ₂m-transgenic C57BL/6 mouse model, we show that human ₂m supports formation and expression of H-2K^b and peptide:H-2K^b complexes at levels nearly equivalent to those in wild-type mice. Despite this finding, the frequencies of CD8⁺ single-positive thymocytes in the thymus and mature CD8⁺ T cells in the periphery were significantly reduced and the TCR V repertoire of peripheral CD8⁺ T cells was skewed in the human ₂m-transgenic mice. Furthermore, the ability of mouse ₂m-restricted CTL to functionally recognize human ₂m⁺ target cells was diminished compared with their ability to recognize mouse ₂m⁺ target cells. Finally, we provide evidence that this effect is achieved through subtle conformational changes occurring in the distal, peptide-binding region of the MHC-I molecule. Our results indicate that alterations in ₂m influence the ability of TCR to engage MHC-I during normal T cell physiology.

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 R.T. is a Michael Smith Senior Scientist and is funded by the Canadian Institutes of Health Research.

² Address correspondence and reprint requests to Dr. Rusung Tan, Department of Pathology and Laboratory Medicine, British Columbia’s Children’s Hospital, 4480 Oak Street, Vancouver, British Columbia, Canada. E-mail address: roo{at}interchange.ubc.ca

³ Abbreviations used in this paper: MHC-I, MHC class I; ₂m, ₂-microglobulin; h, human; m, mouse; MFI, mean fluorescence intensity; DP, double positive; DN, double negative; SP, single positive; LN, lymph node; ES, embryonic stem cell; Tg, transgenic.