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Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. 2012
Philipp A Lang, and
Karl S Lang, and
Haifeng C Xu, and
Melanie Grusdat, and
Ian A Parish, and
Mike Recher, and
Alisha R Elford, and
Salim Dhanji, and
Namir Shaabani, and
Charles W Tran, and
Dilan Dissanayake, and
Ramtin Rahbar, and
Magar Ghazarian, and
Anne Brüstle, and
Jason Fine, and
Peter Chen, and
Casey T Weaver, and
Christoph Klose, and
Andreas Diefenbach, and
Dieter Häussinger, and
James R Carlyle, and
Susan M Kaech, and
Tak W Mak, and
Pamela S Ohashi
Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada M5G 2C1.
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.
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