Natural killer cells act as rheostats modulating antiviral T cells
Open Access
- 20 November 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 481 (7381), 394-398
- https://doi.org/10.1038/nature10624
Abstract
Natural killer cells can act as rheostats, or ‘master regulators’, controlling antiviral T-cell responses. In mice infected with lymphocytic choriomeningitis virus, a model for human hepatitis C virus and human immunodeficiency virus (HIV) infections, natural killer (NK) T cells are shown to regulate antiviral T-cell immunity by directly killing activated CD4 T cells. This immunoregulatory role is in addition to the direct antiviral effects of NK cells. Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection1,2,3, implying that NK cells have a role in these T-cell-associated diseases. Although direct NK-cell-mediated lysis of virus-infected cells may contribute to antiviral defence during some virus infections—especially murine cytomegalovirus (MCMV) infections in mice and perhaps HIV in humans4,5—NK cells have also been suspected of having immunoregulatory functions. For instance, NK cells may indirectly regulate T-cell responses by lysing MCMV-infected antigen-presenting cells6,7. In contrast to MCMV, lymphocytic choriomeningitis virus (LCMV) infection in mice seems to be resistant to any direct antiviral effects of NK cells5,8. Here we examine the roles of NK cells in regulating T-cell-dependent viral persistence and immunopathology in mice infected with LCMV, an established model for HIV and HCV infections in humans. We describe a three-way interaction, whereby activated NK cells cytolytically eliminate activated CD4 T cells that affect CD8 T-cell function and exhaustion. At high virus doses, NK cells prevented fatal pathology while enabling T-cell exhaustion and viral persistence, but at medium doses NK cells paradoxically facilitated lethal T-cell-mediated pathology. Thus, NK cells can act as rheostats, regulating CD4 T-cell-mediated support for the antiviral CD8 T cells that control viral pathogenesis and persistence.Keywords
This publication has 44 references indexed in Scilit:
- HIV-1 adaptation to NK-cell-mediated immune pressureNature, 2011
- Cutting Edge: CD8+ T Cell Priming in the Absence of NK Cells Leads to Enhanced Memory ResponsesThe Journal of Immunology, 2011
- Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesisJCI Insight, 2010
- Innate immunity defines the capacity of antiviral T cells to limit persistent infectionThe Journal of Experimental Medicine, 2010
- Altered NK Cell Development and Enhanced NK Cell-Mediated Resistance to Mouse Cytomegalovirus in NKG2D-Deficient MiceImmunity, 2009
- A Vital Role for Interleukin-21 in the Control of a Chronic Viral InfectionScience, 2009
- IL-21 Is Required to Control Chronic Viral InfectionScience, 2009
- Natural Killer Cells Promote Early CD8 T Cell Responses against CytomegalovirusPLoS Pathogens, 2007
- NK cell functions restrain T cell responses during viral infectionsEuropean Journal of Immunology, 2001
- Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell inductionThe Journal of Experimental Medicine, 1978