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Xenogeneic ₂-Microglobulin Substitution Alters NK Cell Function¹

Loralyn A. Benoît^* 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

Recently, it has been shown that human ₂-microglobulin (h-₂m) blocks the association between the NK cell inhibitory receptor Ly49C and H-2K^b. Given this finding, we therefore sought to assess the immunobiology of NK cells derived from C57BL/6 (H-2^b) mice expressing exclusively h-₂m. Initial analysis revealed that the Ly49C expression profile of NK cells from h-₂m⁺ mice was modified, despite the fact that H-2K^b expression was normal in these mice. Moreover, the NK cells were not anergic in that IL-2 treatment of h-₂m⁺ NK cells in vitro enabled efficient lysis of prototypic tumor cell lines as well as of syngeneic h-₂m⁺ lymphoblasts. This loss of self-tolerance appeared to correlate with the activation status of h-₂m⁺ NK cells because quiescent h-₂m⁺ transplant recipients maintained h-₂m⁺ grafts but polyinosine:polycytidylic acid-treated recipients acutely rejected h-₂m⁺ grafts. NK cell reactivity toward h-₂m⁺ targets was attributed to defective Ly49C interactions with h-₂m:H-2K^b molecules. With regard to NK cell regulatory mechanisms, we observed that h-₂m:H-2K^b complexes in the cis-configuration were inefficient at regulating Ly49C and, furthermore, that receptor-mediated uptake of h-₂m:H-2K^b by Ly49C was impaired compared with uptake of mouse ₂m:H-2K^b. Thus, we conclude that transgenic expression of h-₂m alters self-MHC class I in such a way that it modulates the NK cell phenotype and interferes with regulatory mechanisms, which in turn causes in vitro-expanded and polyinosine:polycytidylic acid-activated NK cells to be partially self-reactive similar to what is seen with NK cells derived from MHC class I-deficient mice.

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 Foundation 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 Children’s Hospital, 4480 Oak Street, Room 2G5, 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; m, mouse; h, human; MFI, mean fluorescent intensity; LAK, lymphokine-activated killer; poly(I:C), polyinosine:polycytidylic acid; Wt, wild type; Tg, transgenic; LU, lytic unit; LN, lymph node.