Li Haiying, Richert-Spuhler Laura E, Evans Tristan I, Gillis Jacqueline, Connole Michelle, Estes Jacob D, Keele Brandon F, Klatt Nichole R, Reeves R Keith
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America.
PLoS Pathog. 2014 Dec 11;10(12):e1004551. doi: 10.1371/journal.ppat.1004551. eCollection 2014 Dec.
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.
HIV/SIV感染会破坏胃肠道黏膜的完整性，并导致慢性免疫激活及相关疾病进展。天然淋巴细胞（ILC）通过高表达NKp44和RORγt得以区分，在黏膜防御和内环境稳定中发挥关键作用，但在慢性SIV感染期间会从胃肠道大肠中耗竭。然而，关于ILC损失的动力学，或者它是否全身性发生，人们了解较少。在急性SIV感染中，我们发现早在感染后第6天，所有黏膜中的NKp44+ILC就大量减少，最多可达8倍，这种减少在慢性疾病阶段持续存在。有趣的是，在黏膜引流淋巴结中未观察到ILC损失。相比之下，经典NK细胞在肠道或引流淋巴结中均未耗竭。通过Annexin-V表达增加来衡量，ILC和NK细胞的凋亡水平均显著升高，但经典NK细胞也显示出增殖增加，而ILC则没有。有趣的是，通常无细胞毒性的ILC在急性和慢性感染中显著上调细胞毒性功能，并获得了分泌IFN-γ、MIP1-β和TNF-α的多功能表型，但原型细胞因子IL-17的产生减少。经典NK细胞的功能变化不那么显著，但穿孔素表达上调，细胞毒性潜力增加。最后，我们表明ILC的数量和功能损失是由于肠道环境中炎症细胞因子诱导的凋亡增加和RORγt抑制。在此，我们首次证明了在SIV感染期间黏膜ILC急性、全身性和永久性损失与IL-17减少相关的证据。ILC的大量减少涉及凋亡且无代偿性的从头发育/增殖，但耗竭的完整机制以及感染早期功能变化的影响仍不清楚。
