Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors

Parikh, B. A.; Bern, M. D.; Piersma, S. J.; Yang, L.; Beckman, D. L.; Poursine-Laurent, J.; Plougastel-Douglas, B.; Yokoyama, W. M. M.

doi:10.1101/753970

bioRxiv · 10.1101/753970

Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors

Parikh, B. A.·Bern, M. D.·Piersma, S. J.·Yang, L.·Beckman, D. L.·Poursine-Laurent, J.·Plougastel-Douglas, B.·Yokoyama, W. M. M.

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Abstract

Viruses have evolved strategies that highlight critical, intertwined host immune mechanisms. As postulated by the missing-self hypothesis, natural killer (NK) cells and major histocompatibility complex class I (MHC-I)-restricted cytotoxic T lymphocytes (CTLs) have opposing requirements for ubiquitously expressed MHC-I molecules. Since NK cell MHC-I-specific Ly49 inhibitory receptors prevent killing of cells with normal MHC-I, viruses evading CTLs by down-regulating MHC-I should be vulnerable to NK cells. However, definitive integrated in vivo evidence for this interplay has been lacking, in part due to receptor polymorphism and a proposed second function of Ly49 receptors in licensing NK cells via self-MHC-I. Here we generated mice lacking specific Ly49 inhibitory receptors to show their essential role in licensing and controlling murine cytomegalovirus (MCMV) infection in vivo in an MHC-restricted manner. When MCMV cannot down-regulate MHC-I, NK cells cannot control infection that instead is mediated by CTLs, as predicted by the missing-self hypothesis.

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Parikh, B. A., Bern, M. D., Piersma, S. J., Yang, L., Beckman, D. L., Poursine-Laurent, J., Plougastel-Douglas, B., Yokoyama, W. M. M.. 2019-09-04. Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors. https://doi.org/10.1101/753970

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