Switch from homeostatic to inflammatory cytokines by NK/ILC in HIV-infected gut

 描述(由申请人提供)：在HIV感染过程中TH22的丢失可能导致肠道中IL-22的存在减少；然而，天然淋巴样细胞(ILCs)的亚群，主要是表达ILC3的NKp44激活受体，即使在T细胞在胃肠道(GI)中耗尽时，也能够维持IL-22的水平。我们的初步数据表明，从病毒型HIV感染者身上获得的肠道自然杀伤细胞(NK)/ILCs(包括那些表达NKp44的细胞)产生干扰素-γ(IFN-j)的频率高于从未感染个体的胃肠道获得的细胞。我们假设HIV创造了一种环境，改变了NK/ILC的功能，从对维持胃肠道内平衡至关重要的细胞，到导致感染患者肠道炎症和屏障功能障碍增加的细胞。我们推测HIV通过1)刺激肠道髓系树突状细胞(MDC)分泌致炎细胞因子2)改变肠道微生物群以增加致病细菌数量，进而触发MDCS分泌更高水平的致炎细胞因子3)诱导CD4T细胞上NKp44的配体表达，从而触发ILC3(通常分泌IL-22)开始分泌IFN-j和TNF-a，以及4)诱导HIV感染的T细胞上的配体表达，进而触发致炎NK/ILC1 s分泌更高水平的促炎细胞因子3，从而触发ILC3(通常分泌IL-22)开始分泌IFN-j和TNF-a，以及4)诱导感染HIV的T细胞上的配体表达，进而触发促炎NK/ILC1s分泌更高水平的促炎细胞因子3)，从而直接或间接地诱导炎性NK/ILC。为了解决这些假说，我们提出了以下特定目标：1：评估未经治疗的HIV感染者肠道NK/ILC细胞因子谱、NK/ILC激活受体配体的表达与上皮屏障功能的关系，以及肠道NK/ILC细胞炎性细胞因子的产生与抑制性CART中HIV感染的临床相关性是否存在关联。特定目的2：确定HIV和HIV改变的粘膜细菌(HAMB)在诱导结肠炎性细胞因子3(ILC3)中的作用机制。目的3：确定HIV和HIV改变的粘膜细菌(HAMB)促进促炎性NK1/ILC1频率增加的机制。

 DESCRIPTION (provided by applicant): Loss of TH22 during HIV infection may contribute to decreased IL-22 presence in the gut; however, a subpopulation of innate lymphoid cells (ILCs), mainly NKp44 activation receptor expressing ILC3, is capable of maintaining IL-22 levels even when T-cells are depleted in the gastrointestinal (GI) tract. Our preliminary data indicate that that there are higher frequencies of gut-derived Natural Killer cells (NK)/ILCs (including those that express NKp44) that produce interferon-gamma (IFN-j) when they were obtained from viremic HIV-infected individuals as compared to cells obtained from the GI tract of uninfected individuals. We hypothesize that HIV creates an environment that alters the function of NK/ILCs from cells that are important in maintaining homeostasis in the GI tract to cells that contribute t increased inflammation and barrier dysfunction in the gut of infected patients. We postulate that HIV both directly and indirectly induces inflammatory NK/ILC by 1) stimulating intestinal myeloid dendritic cells (mDC) to secrete pro-inflammatory cytokines 2) modifying the gut microbiome to increase pathobiont bacteria, which in turn trigger mDCs to secrete higher levels of pro- inflammatory cytokines 3) inducing the expression of ligands to NKp44 on CD4+ T-cells which trigger ILC3s (which normally secrete IL-22) to begin secreting IFN-j and TNF-a and 4) inducing the expression of ligands on HIV-infected T-cells, which in turn, trigger pro-inflammatory NK/ILC1s to secrete IFN-j/TNF-a. To address these hypotheses, we propose the following: Specific Aim 1: To evaluate the relationship between gut NK/ ILC cytokine profiles, expression of NK/ILC activating receptor ligands, and epithelial barrier function in untreated HIV infection and to determine whether associations exist between gut NK/ILC cell inflammatory cytokine production and clinical correlates of HIV pathogenesis in HIV-infected subjects on suppressive cART. Specific Aim 2: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to the induction of colonic inflammatory ILC3s Aim 3: To determine the mechanism in which HIV and HIV-altered mucosal bacteria (HAMB) contribute to increased frequencies of pro-inflammatory NK1/ILC1s.