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Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys

Abstract

Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5+ and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes.

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Figure 1: Numbers and distribution of SIV RNA and NK cells in lymph nodes.
Figure 2: CXCR5 expression on NK cells and phenotyping of CXCR5+ NK cells in AGMs.
Figure 3: Viral load and NK cells in spleen from chronically infected AGMs and macaques.
Figure 4: IL-15 expression in lymph nodes during SIV infection in AGMs and macaques.
Figure 5: Anti-IL-15 administration results in near-complete NK cell depletion in AGMs.
Figure 6: NK cell depletion results in increases in SIV RNA, SIV DNA and productively infected cells in lymph nodes.

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Acknowledgements

This work was supported by the Investissements d'Avenir program managed by the National Agency of Research (ANR) under reference ANR-10-LABX-77, the ANRS and the L'Oréal Foundation. The Infectious Disease Models and Innovative Therapies (IDMIT) center in Fontenay-aux-Roses, France, was funded by the French government's Investissements d'Avenir program for infrastructures (PIA) under grant ANR-11-INBS-0008, the PIA grant ANR-10-EQPX-02-01 funding the FlowCyTech facility at IDMIT. R.K.R. was supported by National Institutes of Health (NIH) grant RO1 DE026014. The anti-IL-15 monoclonal antibody was a gift from the NIH Nonhuman Primate Reagent Resource, supported by AI126683 and OD010976. N.H. and M.J.P. were recipients of postdoctoral fellowships from the French Vaccine Research Institute (Créteil, France) and Sidaction, respectively. P.R. and T.G.-T. received a PhD fellowship from the University Paris Diderot, Sorbonne Paris Cité (BIOSPC), and the Pasteur-Paris University PhD program supported by the Institut Carnot Pasteur Microbes et Santé, respectively. We are grateful to the veterinarians and the staff of the IDMIT animal facility, in particular V. Contreras, B. Delache, J.-M. Helies, V. Monnet, J. Morin and C. Joubert, for their excellent work. We thank L. Irbah, T. Kortulewski and C. Chapon for access to the stellar IDMIT imaging core facility as well as C. Cassan, S. Guenounou and A. Cosma for access to the state-of-the-art IDMIT FlowCyTech core facility.

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N.H. contributed to the project design, set up methods and performed the experiments; N.D.-B. provided samples; N.H., B.J., T.G.-T., P.R. and M.J.P. processed the samples; P.R. prepared the IL15 probe; N.H. and Y.M. performed the statistical analyses; N.H., B.J., R.K.R. and M.M.-T. analyzed and interpreted the data; B.J. prepared the ethical protocols; N.H. and M.M.-T. wrote the manuscript; and M.M.-T. conceived the project and directed the research.

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Correspondence to Michaela Müller-Trutwin.

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Huot, N., Jacquelin, B., Garcia-Tellez, T. et al. Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys. Nat Med 23, 1277–1286 (2017). https://doi.org/10.1038/nm.4421

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