title: 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.
authors.affiliation: Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute,  University Health Network, Toronto, ON,  Canada M5G 2C1.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.forename: Haifeng C
authors.initials: HC
authors.lastname: Xu
authors.forename: Melanie
authors.initials: M
authors.lastname: Grusdat
authors.forename: Ian A
authors.initials: IA
authors.lastname: Parish
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: Salim
authors.initials: S
authors.lastname: Dhanji
authors.forename: Namir
authors.initials: N
authors.lastname: Shaabani
authors.forename: Charles W
authors.initials: CW
authors.lastname: Tran
authors.forename: Dilan
authors.initials: D
authors.lastname: Dissanayake
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahbar
authors.forename: Magar
authors.initials: M
authors.lastname: Ghazarian
authors.forename: Anne
authors.initials: A
authors.lastname: Brüstle
authors.forename: Jason
authors.initials: J
authors.lastname: Fine
authors.forename: Peter
authors.initials: P
authors.lastname: Chen
authors.forename: Casey T
authors.initials: CT
authors.lastname: Weaver
authors.forename: Christoph
authors.initials: C
authors.lastname: Klose
authors.forename: Andreas
authors.initials: A
authors.lastname: Diefenbach
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: James R
authors.initials: JR
authors.lastname: Carlyle
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D003141:Communicable Diseases / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006652:Histological Techniques; D007111:Immunity, Cellular / Q000276:immunology*; D016898:Interferon-alpha / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016898:Interferon-alpha; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K