title: CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients.
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.
authors: INSERM UMR-S 945, Hôpital Pitié Salpêtrière, Paris, France.
authors: Vivien
authors: V
authors: Béziat
authors: Olav
authors: O
authors: Dalgard
authors: Tarik
authors: T
authors: Asselah
authors: Philippe
authors: P
authors: Halfon
authors: Pierre
authors: P
authors: Bedossa
authors: Ali
authors: A
authors: Boudifa
authors: Baptiste
authors: B
authors: Hervier
authors: Ioannis
authors: I
authors: Theodorou
authors: Michelle
authors: M
authors: Martinot
authors: Patrice
authors: P
authors: Debré
authors: Niklas K
authors: NK
authors: Björkström
authors: Karl-Johan
authors: KJ
authors: Malmberg
authors: Patrick
authors: P
authors: Marcellin
authors: Vincent
authors: V
authors: Vieillard
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D001324:Autoantigens / Q000276:immunology; D019002:CD56 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D048708:Cell Growth Processes; D002478:Cells, Cultured; D060966:Clonal Selection, Antigen-Mediated; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000472:pathogenicity; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006521:Hepatitis, Chronic / Q000097:blood / Q000276:immunology* / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism; D054343:Receptors, KIR2DL2 / Q000276:immunology / Q000378:metabolism; D000097625:HLA-E Antigens
chemical_list: D000914:Antibodies, Viral; D001324:Autoantigens; D019002:CD56 Antigen; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054343:Receptors, KIR2DL2; D000097625:HLA-E Antigens; C515077:KIR2DL2 protein, human; C527059:KLRC2 protein, human