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      NKG2C + memory-like NK cells contribute to the control of HIV viremia during primary infection: Optiprim-ANRS 147

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          Abstract

          Natural-killer (NK) cells are important immune effectors during a viral infection. Latent CMV infection is widely spread and was demonstrated to shape the NK cell repertoire through the NKG2C receptor. An expansion of NKG2C + NK cells has been reported during primary HIV infection (PHI), but their role is not known. We previously found a correlation between the maturation state of the NK cell compartment and a lower viral load by studying patients from the ANRS 147 Optiprim trial. We investigated here extensively the NKG2C + NK cells at the time of PHI and its evolution after 3 months of early antiretroviral therapy (combination antiretroviral therapy (cART)). Multiparametric cytometry combined with bioinformatics was used to determine subsets. NK bright NKG2C + progenitor, NK dim NKG2C + effector and NK dim NKG2C +CD57 + memory-like populations were identified. Two groups of patients were unraveled according to the distribution of the NKG2C + subsets skewed toward either progenitor/effector or memory-like phenotype. Patients with high NKG2C +CD57 + NK cell frequencies showed lower HIV-RNA, lower immune activation, higher pDC counts and reached more rapidly undetectable levels of HIV-RNA at M1 under cART. NKG2C +CD57 + NK cell frequency was the only factor strongly correlated to low viral load among other clinical features. While the patients were cytomegalovirus (CMV) infected, there was no sign of reactivation of CMV during PHI suggesting that memory-like NK cells were already present at the time of HIV infection and constituted a preexisting immune response able to contribute to natural control of HIV. This parameter appears to be a good candidate in the search of predictive markers to monitor HIV remission.

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          Most cited references28

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          Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education.

          Natural killer (NK) cells are lymphocytes of the innate immune system that, following differentiation from CD56(bright) to CD56(dim) cells, have been thought to retain fixed functional and phenotypic properties throughout their lifespan. In contrast to this notion, we here show that CD56(dim) NK cells continue to differentiate. During this process, they lose expression of NKG2A, sequentially acquire inhibitory killer cell inhibitory immunoglobulin-like receptors and CD57, change their expression patterns of homing molecules, and display a gradual decline in proliferative capacity. All cellular intermediates of this process are represented in varying proportions at steady state and appear, over time, during the reconstitution of the immune system, as demonstrated in humanized mice and in patients undergoing hematopoietic stem cell transplantation. CD56(dim) NK-cell differentiation, and the associated functional imprint, occurs independently of NK-cell education by interactions with self-human leukocyte antigen class I ligands and is an essential part of the formation of human NK-cell repertoires.
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            Natural killer cell memory in infection, inflammation and cancer.

            Immunological memory can be defined as a quantitatively and qualitatively enhanced immune response upon rechallenge. For natural killer (NK) cells, two main types of memory exist. First, similarly to T cells and B cells, NK cells can exert immunological memory after encounters with stimuli such as haptens or viruses, resulting in the generation of antigen-specific memory NK cells. Second, NK cells can remember inflammatory cytokine milieus that imprint long-lasting non-antigen-specific NK cell effector function. The basic concepts derived from studying NK cell memory provide new insights about innate immunity and could lead to novel strategies to improve treatments for infectious diseases and cancer.
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              Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function.

              During mouse cytomegalovirus (CMV) infection, a population of Ly49H(+) natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C(+) NK cells expanded and were potent producers of IFNγ. NKG2C(+) NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulin-like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56(dim) NK cells. Strikingly, increased frequencies of NKG2C(+) NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C(+) NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.
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                Author and article information

                Journal
                Clin Transl Immunology
                Clin Transl Immunology
                Clinical & Translational Immunology
                Nature Publishing Group
                2050-0068
                July 2017
                07 July 2017
                1 July 2017
                : 6
                : 7
                : e150
                Affiliations
                [1 ]Aix Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, CRCM, Department of Immunity and Cancer , Marseille, France
                [2 ]Department of Internal Medecine, Hôpital Bicêtre, APHP , Le Kremlin-Bicêtre, France
                [3 ]EA 7327 Paris Descartes University , Paris, France
                [4 ]Aix Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, CRCM, CiBi Platform , Marseille, France
                [5 ]Paris-Sud University, U1184 , Le Kremlin-Bicêtre, France
                [6 ]CEA, Department of DSV/iMETI, IDMIT , Fontenay-aux-Roses, France
                [7 ]Inserm U1184, Department of ImVA ‘Immunology of chronic Viral infections and Autoimmune diseases’ , Le Kremlin-Bicêtre, France
                [8 ]Institut Pasteur, HIV, Inflammation and Persistance Unit, Virology Department , Paris, France
                [9 ]Virology Laboratory, APHP CHU Necker-Enfants Malades , Paris, France
                [10 ]Dipartimento di medecina Sperimentale and Centro di Eccellenza per la Ricerca Biomedica, Università di Genova , Genova, Italy
                [11 ]Department of Infectious Diseases APHP, Hôpital Tenon , Paris, France
                [12 ]Inserm, CESP U1018, Univ Paris-Sud, Department of Epidemiology and Population Health, APHP, Hôpital Bicêtre , Le Kremlin-Bicêtre, France
                Author notes
                [* ]Aix Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, CRCM, Department of Immunity and Cancer , 27, boulevard Lei Roure, BP 30059, 13273 Marseille, France. E-mail: francoise.gondois-rey@ 123456inserm.fr or daniel.olive@ 123456inserm.fr
                Author information
                http://orcid.org/0000-0001-9245-1535
                Article
                cti201722
                10.1038/cti.2017.22
                5539415
                28791125
                02ba87a4-cd52-419a-8a2b-10f4a9886aad
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 24 November 2016
                : 06 April 2017
                : 04 May 2017
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