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Natural killer cells act as rheostats modulating antiviral T cells

Nature volume 481, pages 394–398 (2012)Cite this article

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Abstract

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.

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Figure 1: NK cells influence T-cell-dependent pathology and viral persistence during LCMV infection.
Figure 2: LCMV-specific T-cell responses enhanced in NK-cell-depleted mice.
Figure 3: Role of CD4 T cells in NK suppression of antiviral CD8 T cells, viral control and immunopathology.
Figure 4: NK cells rapidly eliminate activated CD4 T cells.

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Acknowledgements

We thank K. Hearn, C. Baer, J. Suschak and P. Afriyie for technical support; K. Daniels and M. Seedhom for insightful discussions; R. Taniguchi and V. Kumar for sharing unpublished observations; and H. Ducharme for mouse husbandry. We thank L. Berg for NKT tetramer, L. Lanier for anti-NKG2D blocking antibody (CX5), B. Polić for Nkg2d−/− mice and M. Exley for Cd1d−/− mice. This work was supported by National Institutes of Health (NIH) training grant AI07349 (S.N.W.) and research grants AI-17672, AI-081675, CA34461 (R.M.W.), AI46578 (L.K.S.), a German Research Foundation fellowship CO310-2/1 (M.C.) and an institutional Diabetes Endocrinology Research Center (DERC) grant DK52530. The views expressed are those of the authors and do not necessarily express the views of the NIH.

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Authors and Affiliations

  1. Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA

    Stephen N. Waggoner, Liisa K. Selin & Raymond M. Welsh

  2. Department of Gastroenterology and Hepatology, Medizinische Hochschule, 30625, Hannover, Germany

    Markus Cornberg

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  1. Stephen N. Waggoner
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  2. Markus Cornberg
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  4. Raymond M. Welsh
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Contributions

S.N.W. designed the study, performed experiments, analysed data and wrote the manuscript; R.M.W. designed the study, analysed data and wrote the manuscript; M.C. and L.K.S. were involved in study design, discussed results and commented on the manuscript.

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Correspondence to Raymond M. Welsh.

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The authors declare no competing financial interests.

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Waggoner, S., Cornberg, M., Selin, L. et al. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481, 394–398 (2012). https://doi.org/10.1038/nature10624

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