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      From Natural Killer Cell Receptor Discovery to Characterization of Natural Killer Cell Defects in Primary Immunodeficiencies

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          Abstract

          Alessandro Moretta was Professor of Histology at University of Brescia from 1994 to 1997. It was in that period that we met and started a collaboration that continued in the years to follow. He immediately involved us in the production of monoclonal antibodies (mAbs) that allowed the identification and fine characterization of novel receptor molecules that were able to activate or inhibit human Natural Killer cell function, including several antibodies specific for Natural Cytotoxicity Receptor (NCR) and Killer-cell Immunoglobulin-like Receptor (KIR) molecules. These reagents, generated in our laboratory in Brescia, contributed to complete the studies aimed to characterize innate lymphoid NK cells, that had been initiated by Alessandro and his brother Lorenzo in Genoa. Soon, we identified an anti-KIR3DL2 that was subsequently shown to be helpful for the diagnosis and treatment of various forms of cutaneous T cell lymphoma. While in Brescia, Alessandro established a partnership with those of us who were working in the Department of Pediatrics; together, in short time we tackled the goal of studying the role of NK cells in patients with primary immunodeficiencies. This collaboration led to novel discoveries that shed light on the critical role played by NK cells in the immune response against virus and tumors in humans, as best exemplified by our characterization of the molecular mechanisms of impaired control of Epstein-Barr Virus (EBV) infection in patients with X-linked lymphoproliferative (XLP) disease. After Alessandro left Brescia to return to Genoa, our collaboration continued with the same enthusiasm, and even from a distance he remained an extraordinary example of an inspirational and generous mentor. This review is a sign of our gratitude to a mentor and a friend whom we deeply miss.

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          Most cited references43

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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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            CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset.

            Natural killer (NK) cells are innate immune lymphocytes that express a heterogeneous repertoire of germline-encoded receptors and undergo a distinct pattern of maturation. CD57 is a marker of terminal differentiation on human CD8(+) T cells. Very few newborn or fetal NK cells express CD57; however, the frequency of CD57-bearing NK cells increases with age. We assessed the transcriptional, phenotypic, and functional differences between CD57(+) and CD57(-) NK cells within the CD56(dim) mature NK subset. CD57(+) NK cells express a repertoire of NK-cell receptors, suggestive of a more mature phenotype, and proliferate less when stimulated with target cells and/or cytokines. By contrast, a higher frequency of CD57(+) NK cells produced interferon-γ and demonstrated more potent lytic activity when these cells were stimulated through the activating receptor CD16; however, they are less responsive to stimulation by interleukin-12 and interleukin-18. Finally, CD57 expression is induced on CD57(-)CD56(dim) NK cells after activation by interleukin-2. A combination of a mature phenotype, a higher cytotoxic capacity, a higher sensitivity to stimulation via CD16, with a decreased responsiveness to cytokines, and a decreased capacity to proliferate suggest that CD57(+) NK cells are highly mature and might be terminally differentiated.
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              Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals.

              Natural killer (NK) cells are an important component of the innate immune response against viral infections. NK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(-)/CD16(+) (CD56(-)) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory NK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56(-) NK fraction compared with that of CD56(+) NK cells was associated with extremely poor in vitro cytotoxic function of this subset. In addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56(-), as compared with the CD56(+) NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56(-) NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total NK cell population.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                24 July 2019
                2019
                : 10
                : 1757
                Affiliations
                [1] 1Department of Molecular and Translational Medicine, University of Brescia , Brescia, Italy
                [2] 2Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, United States
                [3] 3Department of Experimental and Clinical Sciences, University of Brescia , Brescia, Italy
                Author notes

                Edited by: Eric Vivier, INSERM U1104 Centre d'Immunologie de Marseille-Luminy, France

                Reviewed by: Karl-Johan Malmberg, Oslo University Hospital, Norway; Stephen Noel Waggoner, Cincinnati Children's Hospital Medical Center, United States

                *Correspondence: Silvia Parolini silvia.parolini@ 123456unibs.it

                This article was submitted to NK and Innate Lymphoid Cell Biology, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                ‡These authors share senior authorship

                Article
                10.3389/fimmu.2019.01757
                6668486
                641f7bfe-f549-4366-8380-2d23086c9d2f
                Copyright © 2019 Tabellini, Patrizi, Dobbs, Lougaris, Baronio, Coltrini, Plebani, Badolato, Notarangelo and Parolini.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 May 2019
                : 11 July 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 64, Pages: 11, Words: 9097
                Categories
                Immunology
                Review

                Immunology
                natural killer cells,primary immunodeficiencies,monoclonal antibodies,functional assays,signaling transduction

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