Loss and aberrant function of NKp44+ ILCs in the SIV-infected gut are associated with RORγt suppression (P6175)

Abstract

Abstract Recent studies have identified a novel NK cell-like population found in mucosal tissues and mucosae-draining lymph nodes distinguishable by high surface expression of NKp44 and referred to as innate lymphoid cells (ILCs). ILCs secrete IL-17/IL-22 which are critical for epithelial homeostasis and thus could play a role in gut integrity, a major factor in HIV/SIV pathogenesis. During chronic SIV infection, numbers of ILCs declined ~8-fold in gastrointestinal tissues, but remained comparable to naïve animals in distal sites such as mesenteric lymph nodes and lungs. Loss of ILCs was associated with up to 100-fold increases in apoptosis. Interestingly, gut ILCs expressed NFIL3, a classic NK cell-related transcription factor, as well as the IL-17 transcriptional regulator, RORγt, but during SIV infection RORγt was significantly downregulated associated with decreased IL-17 secretion. In these same animals increased IFN-γ secretion and acquired cytotoxicity were associated with an increase in ILC NFIL3. Loss and functional skewing of ILCs in vivo correlated with upregulated IDO-1 and IFN-α in the gut, and in vitro treatment of ILCs with IDO-1 catabolites and IFN-α also suppressed RORγt expression, ablated IL-17 production and induced apoptosis. SIV infection results in massive numerical and functional depletion of ILCs in the inflamed gut, but not distal sites. This phenomenon was due, at least in part, to IDO-1- and IFN-α-induced apoptosis and suppression of RORγt.