Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 + T-cell immunity
- 13 December 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (4), 1210-1215
- https://doi.org/10.1073/pnas.1118834109
Abstract
Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3−/−, E4BP4−/−) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.Keywords
This publication has 50 references indexed in Scilit:
- Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesisJCI Insight, 2010
- Natural Killer Cells Are Polarized Toward Cytotoxicity in Chronic Hepatitis C in an Interferon-Alfa–Dependent MannerGastroenterology, 2010
- Nfil3/E4bp4 is required for the development and maturation of NK cells in vivoThe Journal of Experimental Medicine, 2009
- The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell developmentNature Immunology, 2009
- Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infectionThe Journal of Experimental Medicine, 2009
- Natural killer cell function is intact after direct exposure to infectious hepatitis C virionsHepatology, 2008
- Up on the tightrope: natural killer cell activation and inhibitionNature Immunology, 2008
- Lymphocytic Choriomeningitis Virus (LCMV): Propagation, Quantitation, and StorageCurrent Protocols in Microbiology, 2008
- Interleukin-10 determines viral clearance or persistence in vivoNature Medicine, 2006
- Severe Herpesvirus Infections in an Adolescent without Natural Killer CellsThe New England Journal of Medicine, 1989