title: Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection.
abstract: Natural killer (NK) cells are classically viewed as effector cells that kill virus-infected and neoplastic cells, but recent studies have identified a rare mucosal NK- cell subpopulation secreting the TH17 cytokine IL-22. Here, we report identification of 2 distinct lineages of mucosal NK cells characterized as NKG2A(+)NFIL3(+)RORC(-) and NKp44(+)NFIL3(+)RORC(+). NKG2A(+) NK cells were systemically distributed, cytotoxic, and secreted IFN-γ, whereas NKp44(+) NK cells were mucosae-restricted, noncytotoxic, and produced IL-22 and IL-17. During SIV infection, NKp44(+) NK cells became apoptotic, were depleted, and had an altered functional profile characterized by decreased IL-17 secretion; increased IFN-γ secretion; and, surprisingly, increased potential for cytotoxicity. NKp44(+) NK cells showed no evidence of direct SIV infection; rather, depletion and altered function were associated with SIV-induced up-regulation of inflammatory mediators in the gut, including indoleamine 2,3-dioxygenase 1. Furthermore, treatment of NKp44(+) NK cells with indoleamine 2,3-dioxygenase 1 catabolites in vitro ablated IL-17 production in a dose-dependent manner, whereas other NK-cell functions were unaffected. Thus lentiviral infection both depletes and modifies the functional repertoire of mucosal NK cells involved in the maintenance of gut integrity, a finding that highlights the plasticity of this rare mucosal NK-cell population.
authors.affiliation: Divisions of Immunology, New England Primate Research Center, Harvard Medical School, Southborough, MA, USA.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Reeves
authors.forename: Premeela A
authors.initials: PA
authors.lastname: Rajakumar
authors.forename: Tristan I
authors.initials: TI
authors.lastname: Evans
authors.forename: Michelle
authors.initials: M
authors.lastname: Connole
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gillis
authors.forename: Fay E
authors.initials: FE
authors.lastname: Wong
authors.forename: Yury V
authors.initials: YV
authors.lastname: Kuzmichev
authors.forename: Angela
authors.initials: A
authors.lastname: Carville
authors.forename: R Paul
authors.initials: RP
authors.lastname: Johnson
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects* / Q000276:immunology; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018928:Immunity, Mucosal / Q000187:drug effects* / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008253:Macaca mulatta; D055629:Natural Cytotoxicity Triggering Receptor 2 / Q000276:immunology; D061251:Primary Cell Culture; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000254:growth & development; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D000097043:Interleukin-22
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic; D000097043:Interleukin-22