Gut inflammation and indoleamine deoxygenase inhibit IL-17 production and promote cytotoxic potential in NKp44+ mucosal NK cells during SIV infection

RK Reeves, PA Rajakumar, TI Evans… - Blood, The Journal …, 2011 - ashpublications.org
RK Reeves, PA Rajakumar, TI Evans, M Connole, J Gillis, FE Wong, YV Kuzmichev
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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