Dataset Information

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

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.

SUBMITTER: Lang PA

PROVIDER: S-EPMC3268324 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lang Philipp A PA Lang Karl S KS Xu Haifeng C HC Grusdat Melanie M Parish Ian A IA Recher Mike M Elford Alisha R AR Dhanji Salim S Shaabani Namir N Tran Charles W CW Dissanayake Dilan D Rahbar Ramtin R Ghazarian Magar M Brüstle Anne A Fine Jason J Chen Peter P Weaver Casey T CT Klose Christoph C Diefenbach Andreas A Häussinger Dieter D Carlyle James R JR Kaech Susan M SM Mak Tak W TW Ohashi Pamela S PS

Proceedings of the National Academy of Sciences of the United States of America 20111213 4

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 exhib ...[more]

PMID: 22167808

Similar Datasets

Project description:Understanding the mechanisms that help promote protective immune responses to pathogens is a major challenge in biomedical research and an important goal for the design of innovative therapeutic or vaccination strategies. While natural killer (NK) cells can directly contribute to the control of viral replication, whether, and how, they may help orchestrate global antiviral defense is largely unknown. To address this question, we took advantage of the well-defined molecular interactions involved in the recognition of mouse cytomegalovirus (MCMV) by NK cells. By using congenic or mutant mice and wild-type versus genetically engineered viruses, we examined the consequences on antiviral CD8 T cell responses of specific defects in the ability of the NK cells to control MCMV. This system allowed us to demonstrate, to our knowledge for the first time, that NK cells accelerate CD8 T cell responses against a viral infection in vivo. Moreover, we identify the underlying mechanism as the ability of NK cells to limit IFN-alpha/beta production to levels not immunosuppressive to the host. This is achieved through the early control of cytomegalovirus, which dramatically reduces the activation of plasmacytoid dendritic cells (pDCs) for cytokine production, preserves the conventional dendritic cell (cDC) compartment, and accelerates antiviral CD8 T cell responses. Conversely, exogenous IFN-alpha administration in resistant animals ablates cDCs and delays CD8 T cell activation in the face of NK cell control of viral replication. Collectively, our data demonstrate that the ability of NK cells to respond very early to cytomegalovirus infection critically contributes to balance the intensity of other innate immune responses, which dampens early immunopathology and promotes optimal initiation of antiviral CD8 T cell responses. Thus, the extent to which NK cell responses benefit the host goes beyond their direct antiviral effects and extends to the prevention of innate cytokine shock and to the promotion of adaptive immunity.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets