CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients |
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Authors: | Béziat Vivien Dalgard Olav Asselah Tarik Halfon Philippe Bedossa Pierre Boudifa Ali Hervier Baptiste Theodorou Ioannis Martinot Michelle Debré Patrice Björkström Niklas K Malmberg Karl-Johan Marcellin Patrick Vieillard Vincent |
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Institution: | 1. INSERM UMR‐S 945, H?pital Pitié Salpêtrière, Paris, France;2. Université Pierre et Marie Curie, Paris, Paris, France;3. Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden;4. Service d'Hépatologie, Centre de Recherche INSERM CRB3, H?pital Beaujon, Clichy, France;5. Medical Department, Rikshospitalet University Hospital, Oslo, Norway;6. Laboratoire ALPHABIO, H?pital Ambroise Paré, Marseille, France;7. Service d'Anatomie Pathologique, Centre de Recherche INSERM CRB3, H?pital Beaujon, Clichy, France;8. Laboratoire d'Immunologie Cellulaire et Tissulaire, Paris, France;9. Université Pierre et Marie Curie, Paris, Paris, FranceThese authors are senior co‐authors. |
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Abstract: | Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C(+) CD56(dim) NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi-color flow cytometry revealed that the expanded NKG2C(+) CD56(dim) NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-γ, and TNF-α) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C(+) CD56(dim) NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells. |
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Keywords: | CMV HBV HCV KIR Natural killer cells NK cell education NKG2C |
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