Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity

Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1210-5. doi: 10.1073/pnas.1118834109. Epub 2011 Dec 13.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Arenaviridae Infections / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Chronic Disease*
  • Communicable Diseases / immunology*
  • Cytotoxicity Tests, Immunologic
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Histological Techniques
  • Immunity, Cellular / immunology*
  • Interferon-alpha / metabolism
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation / immunology*
  • Lymphocytic choriomeningitis virus*
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • Real-Time Polymerase Chain Reaction


  • Interferon-alpha
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily K