Natural killer (NK) cells provide important host defense against herpesvirus infections and influence subsequent T cell control of replication and maintenance of latency. NK cells exhibit phases of expansion, contraction and memory formation in response to the natural mouse pathogen murine cytomegalovirus (MCMV). Innate and adaptive immune responses are tightly regulated in mammals to avoid excess tissue damage while preventing acute and chronic viral disease and assuring resistance to reinfection. Caspase (CASP)8 is an autoactivating aspartate-specific cysteine protease that initiates extrinsic apoptosis and prevents receptor interacting protein (RIP) kinase (RIPK)1–RIPK3-driven necroptosis. CASP8 also promotes death-independent signal transduction. All of these activities make contributions to inflammation. Here, we demonstrate that CASP8 restricts NK cell expansion during MCMV infection but does not influence NK memory. Casp8−/−Ripk3−/− mice mount higher NK response levels than Casp8+/−Ripk3−/− littermate controls or WT C57BL/6 J mice, indicating that RIPK3 deficiency alone does not contribute to NK response patterns. MCMV m157-responsive Ly49H+ NK cells support increased expansion of both Ly49H− NK cells and CD8 T cells in Casp8−/−Ripk3−/− mice. Surprisingly, hyperaccumulation of NK cells depends on the pronecrotic kinase RIPK1. Ripk1−/−Casp8−/−Ripk3−/− mice fail to show the enhanced expansion of lymphocytes observed in Casp8−/−Ripk3−/− mice even though development and homeostasis are preserved in uninfected Ripk1−/−Casp8−/−Ripk3−/− mice. Thus, CASP8 naturally regulates the magnitude of NK cell responses in response to infection where strong activation signals depend on another key regulator of death signaling, RIPK1. In addition, the strong NK cell response promotes survival of effector CD8 T cells during their expansion. Thus, hyperaccumulation of NK cells and crosstalk with T cells becomes amplified in the absence of extrinsic cell death machinery.
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We thank Sam Speck (Emory University) and Rafi Ahmed (Emory University) for reagents and discussion and Wolfram Brune (Heinrich Pette Institute) for ∆m157 MCMV. This research was supported the National Institute of Health (NIH) Tetramer Core Facility for MHC class I tetramers and the Emory Vaccine Center Flow Core for materials and Public Health Service Grants R01 AI020211 and AI118853 (to E.S.M.) as well as AI068129 (to L.L.L.).
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The authors declare they have no conflict of interest.
Animal experiments were approved according to the United States Public Health Service National Institutes of Health and Emory University Institutional Animal Care and Use Committee guidelines.
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This article is part of the Special Issue on Immunological Imprinting during Chronic Viral Infection.
Edited by: Matthias J. Reddehase.
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Feng, Y., Daley-Bauer, L.P., Roback, L. et al. Caspase-8 restricts natural killer cell accumulation during MCMV Infection. Med Microbiol Immunol 208, 543–554 (2019). https://doi.org/10.1007/s00430-019-00617-6
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