Person:

Li, Haiying

HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-β, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear.

Despite the fact that the majority of human pathogens are transmitted across mucosal surfaces, including the oral mucosae, oral immunity is poorly understood. Furthermore, because the normal flora of the oral cavity is vast and significantly diverse, host immunity must balance a complex system of tolerance and pathogen recognition. Due to the rapid recognition and response to pathogens, the innate immune system, including natural killer (NK) cells, likely plays a critical role in mediating this balance. Because logistical and ethical restraints limit access to significant quantities of human mucosal tissues, non-human primate models offer one of the best opportunities to study mucosal NK cells. In this study we have identified both classical NK cells, as well as innate lymphoid cells (ILCs) in tonsillar and buccal tissues and oral-draining lymph nodes. Identified by mutually exclusive expression of NKG2A and NKp44, NK cells, and ILCs in the oral mucosa are generally phenotypically and functionally analogous to their gut counterparts. (NKG2A^+) NK cells were more cytotoxic while (NKp44^+) ILCs produced copious amounts of IL-17 and TNF-α. However, in contrast to gut, oral NK cells and ILCs both produced large quantities of IFN-γ and the beta-chemokine, MIP-1β. Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils. These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease. Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and limiting transmission of oral mucosal pathogens.