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      Editorial: Role of HLA and KIR in Viral Infections

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          Abstract

          The Editorial on the Research Topic Role of HLA and KIR in Viral Infections The immune system continuously protects its host against pathogens. During viral infections, both innate and adaptive immune cells contribute to an effective immune response. Natural killer (NK) cells can respond quickly to eliminate pathogens and infected cells and suppress dissemination to other tissues. Subsequently, activation of virus-specific CD8+ cytotoxic T cells results in specific killing of infected cells and activation of virus-specific CD4+ T cells further supports the immune response. Human leukocyte antigens (HLA) play an essential role in activation of both NK cells and T cells. This research topic contains eight articles highlighting the latest insights into the various effects of HLA molecules on both NK cell and T-cell reactivity upon viral infection. Natural Killer cell activation is regulated by a variety of activating and inhibitory receptors, including killer-cell immunoglobulin-like receptors (KIRs). KIRs bind to HLA class I molecules, which are expressed on all nucleated cells. As HLA and KIR molecules are highly polymorphic, each individual expresses a unique set of these molecules. The wide range of combinations of HLA and KIR expression results in differences in binding strengths and variation in NK cell activation (1). In this research topic, a review by Walter and Ansari illuminates the associations of HLA and KIR polymorphisms with the outcome of experimental simian immunodeficiency virus infection in rhesus macaques, a model used to study human immunodeficiency virus (HIV) infection. Not only do these associations show which interactions contribute to disease resistance, they also pinpoint combinations that increase susceptibility to disease. Such associations of HLA and KIR with disease progression have also been found in hepatitis C virus (HCV) infection. In her review, Gardiner summarizes current insights into these associations, and further illustrates how NK cells modulate disease outcome in HCV infection. Furthermore, this review highlights the ongoing search for the NK cell subsets required for protective host responses. In addition to KIRs, NK cells express C-type lectin receptors, including NKG2C, which regulate activation via ligation to non-classical HLA-E molecules. Della Chiesa et al. summarize the role of activating KIRs and NKG2C in several virus infections, including human cytomegalovirus (HCMV) and HIV. In addition, they discuss the induction of memory-like NK cells, which show enhanced responses upon reinfection and may play a role in controlling recurrent or chronic infections. Expression of NKG2C has also been associated with expansion of NK cells during viral infection. This expansion of NKG2C+ NK cells with expression of self-HLA class I-specific KIRs has been observed in HCMV infection (2). The force driving these NK cell expansions is largely unclear. In this collection, Beziat et al. investigate the importance of HLA class I expression levels in host defense using data derived from transporter associated with antigen processing (TAP)-deficient individuals who express less than 10% of normal HLA class I levels. They demonstrate that self-HLA class I molecules shape the KIR repertoire of NKG2C+ NK cells, but are not a requirement for expansion. Besides influencing innate NK responses via ligation to KIRs, HLA induces adaptive immune responses by presenting pathogen-derived peptides to T cells. Recognition of HLA:peptide complexes by a peptide-specific T-cell receptor leads to activation of specific CD8+ cytotoxic T cells or CD4+ T helper cells. In HCMV infection, effective CD8+ T-cell responses have been shown to be dominated by peptides derived from immediate-early 1 (IE-1) protein (3–5). Whether IE-1 is also the dominant peptide source for CMV-specific CD4+ T cell responses is unclear. Using cells derived from healthy HCMV-positive donors, Ameres et al. generated multiple IE-1-specific CD4+ T cell clones with a highly diverse repertoire and found that IE-1-specific CD4+ T cells participate in the antiviral response. Since both CD4+ and CD8+ T cells respond to IE-1-derived peptides, it might be an interesting target for immunotherapeutic approaches. Infection with measles virus is known to induce a strong T cell response (6, 7), but information regarding the specific measles virus antigens that are responsible for activation of these cells is limited. Schellens et al. investigated which measles peptides are presented by HLA class I molecules by eluting naturally presented peptides from virus-infected cells. They show that a broad spectrum of the measles peptidome is presented by different HLA class I molecules. Furthermore, they found that while HLA-B molecules present the most diverse set of peptides, the abundant epitopes were eluted from HLA-A and HLA-C molecules, suggesting that the HLA loci also influence peptide presentation. Due to the polymorphic nature of HLA molecules, a great diversity of peptides are typically presented, resulting in T-cell activation of variable strengths. In HCV infections, some HLA molecules (e.g., HLA-B27 and HLA-B57) are significantly associated with viral clearance (8, 9). However, it is not yet known why such HLA molecules provide an advantage during HCV infections. Using known HCV epitopes combined with in silico predictions, Rao et al. demonstrate that HLA-B27 preferentially presents epitopes from the HCV protein NS5B, which is highly conserved and, therefore, might be one of the underlying mechanisms behind the protective effect of this molecule during HCV infection. Preferential presentation of peptides derived from conserved regions was also found for HIV (10–12). However, the induction of effective immune responses also puts pressure on the virus to adapt toward escape variants. The generation of escape variants often comes with significant costs, such as reduced viral replicative capacity. In the final paper of this issue, a review by KlØverpris et al. illustrates the effects of viral escape variants within the HIV-infected patient as well as the consequences of transmission of these variants at the population level. Together, the research and reviews in this research topic provide an up-to-date overview of the importance of HLA and KIR molecules in host responses to viral infection. Given the central role of HLA in modulating both innate and adaptive immune responses, it is important to expand our knowledge on the role of different HLA molecules in various diseases. A better understanding of the differences between the individual immune responses, especially when it fails to protect against pathogens, should ultimately help to develop better – and possibly more individualized – treatment options. Author Contributions JW, JB, CK, and DB wrote the editorial. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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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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            Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function

            Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand–receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR–HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population.
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              Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution.

              Virus-specific CD8+ T cell responses play an important role in the natural course of infection; however, the impact of certain CD8+ T cell responses in determining clinical outcome has not been fully defined. A well-defined cohort of women inoculated with HCV from a single source showed that HLA-B27 has a strong association with spontaneous clearance. The immunological basis for this association is unknown. However, the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection. We report the identification of an HLA-B27 restricted hepatitis C virus (HCV)-specific CD8+ T cell epitope that is recognized in the majority of recovered HLA-B27 positive women. In chronically HCV-infected individuals, analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27, indicating allele-specific selection pressure at the population level. Functional analysis in 3 chronically HCV-infected patients showed that the emerging variant viral epitopes represent escape mutations. In conclusion, our results suggest a dominant role of HLA-B27 in mediating spontaneous viral clearance as well as viral evolution in HCV infection and mechanistically link both associations to a dominant novel CD8+ T cell epitope. These results support the central role of virus-specific CD8+ T cells and the genetically determined restriction of the virus-specific T cell repertoire in HCV infection.
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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
                27 July 2016
                2016
                : 7
                : 286
                Affiliations
                [1] 1Department of Immune Mechanisms, Centre for Infectious Disease Control, National Institute for Public Health and the Environment , Bilthoven, Netherlands
                [2] 2Laboratory of Translational Immunology, Department of Immunology, University Medical Center , Utrecht, Netherlands
                [3] 3Theoretical Biology and Bioinformatics, Utrecht University , Utrecht, Netherlands
                Author notes

                Edited and Reviewed by: Ian Marriott, University of North Carolina at Charlotte, USA

                *Correspondence: Debbie van Baarle, debbie.van.baarle@ 123456rivm.nl

                Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2016.00286
                4961690
                27512394
                f2c1e489-8474-43e2-98d2-9ca3eb113315
                Copyright © 2016 de Wit, Borghans, Kesmir and van Baarle.

                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) or licensor 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
                : 17 May 2016
                : 14 July 2016
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 12, Pages: 2, Words: 1702
                Funding
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek 10.13039/501100003246
                Award ID: 823.02.014
                Categories
                Immunology
                Editorial

                Immunology
                killer ig-like receptors,human leukocyte antigen,t cell receptor,natural killer cells,antiviral immune responses

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