title: NK cells inhibit humoral immunity by reducing the abundance of CD4+ T follicular helper cells during a chronic virus infection.
abstract: There is a need to understand better how to improve B cell responses and immunity to persisting virus infections, which often cause debilitating illness or death. People with chronic virus infection show evidence of improved virus control when there is a strong neutralizing antibody response, and conversely, B cell dysfunction is associated with higher viral loads. We showed previously that NK cells inhibit CD4(+) and CD8(+) T cell responses to disseminating LCMV infection and that depletion of NK cells attenuates chronic infection. Here, we examined the effect of NK cell depletion on B cell responses to LCMV infection in mice. Whereas mice infected acutely generated a peak level of antibody soon after the infection was resolved, mice infected chronically showed a continued increase in antibody levels that exceeded those after acute infection. We found that early NK cell depletion rapidly increased virus-specific antibody levels to chronic infection, and this effect depended on CD4(+) T cells and was associated with elevated numbers of CXCR5(+)CD4(+) TFH cells. However, the NK cell-depleted mice controlled the infection and by 1 mo pi, had lower TFH cell numbers and antibody levels compared with mice with sustained infection. Finally, we show that NK cell depletion improved antiviral CD8(+) T cell responses only when B cells and virus-specific antibody were present. Our data indicate that NK cells diminish immunity to chronic infection, in part, by suppressing TFH cell and antibody responses.
authors.affiliation: *Department of Genetics and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Cook
authors.affiliation: *Department of Genetics and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Kline
authors.affiliation: *Department of Genetics and Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA jwhitmir@email.unc.edu.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Whitmire
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D014777:Virus Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1
keywords: antibody; host defense; immune regulation; lymphocytic choriomeningitis virus; mice