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Cutting Edge: Viral Infection Breaks NK Cell Tolerance to "Missing Self"¹

Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, CA 94143

NK cells attack cells lacking MHC class I, yet MHC class I-deficient mice have normal numbers of NK cells with intact, albeit diminished, functions. Moreover, wild-type NK cells are tolerant of MHC class I-deficient cells in mixed bone marrow chimeras. In this study, we investigated how the absence of MHC class I affects NK cells. NK cells from β₂-microglobulin-deficient (B2m^–/–) and wild-type mice exhibit similar phenotypic and functional characteristics. Both B2m^–/– and wild-type Ly49H⁺ NK cells proliferated robustly and produced IFN- after infection with mouse CMV. NK cells in mixed wild-type:B2m^–/– chimeric mice were initially tolerant of MHC class I-deficient host cells. However, this tolerance was gradually lost over time and after mouse CMV infection was rapidly broken, with a pronounced rejection of host B2m^–/– hematopoietic cells. Thus, although NK cells can be held in check against "missing self," acute inflammation driven by infection can rapidly break established self-tolerance.

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 National Institutes of Health Grant AI068129 supported this work. J.C.S. is supported by the Irvington Institute for Immunological Research. L.L.L. is an American Cancer Society Research Professor.

² Address correspondence and reprint requests to Dr. Lewis Lanier, Department of Microbiology and Immunology, University of California 513 Parnassus Avenue, Box 0414, Health Sciences East 1001G, San Francisco, CA 94143. E-mail address: Lewis.Lanier{at}ucsf.edu

³ Abbreviations used in this paper: B2m^–/–, β₂-microglobulin deficient; B6, C57BL/6; KLRG1, killer cell lectin-like receptor G1; MCMV, mouse CMV.

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