1. Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection.
- Author
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Reeves RK, Rajakumar PA, Evans TI, Connole M, Gillis J, Wong FE, Kuzmichev YV, Carville A, and Johnson RP
- Subjects
- Animals, Cell Lineage immunology, Cytotoxicity, Immunologic immunology, Flow Cytometry, Gastric Mucosa immunology, Gastric Mucosa metabolism, Immunity, Mucosal immunology, Inflammation metabolism, Inflammation pathology, Inflammation virology, Interferon-gamma biosynthesis, Interleukin-17 biosynthesis, Interleukins biosynthesis, Killer Cells, Natural cytology, Killer Cells, Natural metabolism, Macaca mulatta, Natural Cytotoxicity Triggering Receptor 2 immunology, Primary Cell Culture, Receptors, Immunologic genetics, Receptors, Immunologic immunology, Receptors, Immunologic metabolism, Simian Acquired Immunodeficiency Syndrome metabolism, Simian Acquired Immunodeficiency Syndrome pathology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus drug effects, Simian Immunodeficiency Virus growth & development, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, Viral Load drug effects, Virus Replication drug effects, Interleukin-22, Cytotoxicity, Immunologic drug effects, Gastric Mucosa drug effects, Immunity, Mucosal drug effects, Indoleamine-Pyrrole 2,3,-Dioxygenase pharmacology, Inflammation immunology, Interleukin-17 antagonists & inhibitors, Killer Cells, Natural immunology, Simian Acquired Immunodeficiency Syndrome immunology, T-Lymphocyte Subsets immunology
- 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.
- Published
- 2011
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