HIV-1慢性感染I型干扰素介导肠道3型天然淋巴细胞功能损伤的机制研究

It is very important to elucidate the immune mechanisms underlying the loss of gut barrier in chronic HIV infection. Recent studies have shown that HIV-1 infection mainly depleted intestinal CD4 T cells and impaired their abilities to produce interleukin-22 (IL-22), thus increasing the intestinal permeability, and promoting disease progression. Our previous study published on J Clin Invest indicated that chronic HIV-1 infection largely depleted group-3 innate lymphoid cells (ILC3s) and reduced their IL-22 production in both peripheral blood and gut mucosal as compared with that of healthy subjects. This numberial and functional impairment of ILC3s was further found to be closely associated with plasmacytoid dendritic cells (pDCs) because the depletion of pDCs significantly recovered the ILC3 impairment in chronic HIV-1 infection. More important, we found that I-IFN pretreatment significantly inhibited IL-22 production by ILC3s in response to AHR ligand stimulation in vitro. Basing on these data, we proposed a hypothesis that the decreased IL-22 production by ILC3 cells may be due to the decreased AHR signaling, on some extent dependent on I-IFN, which thus further leading to the loss of intestinal epithelial cell barrier and the spread of a mount of bacterial products such as LPS into circulation. This study highlights the key role of I-IFN in the mediation of ILC3 impairment in the pathogenesis of HIV-1 infection and will provide a novel therapeutic strategy targeting ILC3s or associated signal pathway in chronic HIV-1 infection.

阐明HIV-1感染肠道免疫屏障损伤的发生机制具有重要意义。研究表明HIV-1感染主要删除肠道CD4 T细胞，尤其损伤其IL-22产生能力，进而导致肠道粘膜屏障受损。我们前期发表在J Clin Invest结果显示，HIV-1慢性感染导致3型天然淋巴细胞（ILC3s）删除及其IL-22分泌功能降低，删除浆样树突细胞（pDCs）可逆转上述损伤。进一步发现，I型干扰素（I-IFN）能抑制芳香烃受体(AHR)刺激剂诱导ILC3s分泌IL-22的能力。据此，我们假设HIV-1慢性感染通过激活pDCs，诱导I-IFN产生，后者进一步损伤了ILC3s对AHR信号的反应性，最终导致ILC3s功能损伤、肠粘膜免疫屏障减弱、细菌产物大量入侵引起免疫超活化、推动疾病进展。该研究将阐明I-IFN依赖的ILC3s功能抑制在HIV-1感染肠道免疫屏障损伤中的关键作用，也为研制靶向ILC3s的新型治疗策略提供科学依据。

免疫细胞是机体抗病毒最重要的武器之一。既往研究表明，HIV-1感染可诱导免疫细胞凋亡及功能损伤。其机制一直聚焦在病毒蛋白成分的直接作用，而机体免疫系统的调节机制一直未完全阐明。本项目研究的主要内容包括：利用HIV-1感染者组织标本库和人源化小鼠模型，阐明了HIV-1感染可通过激活浆样树突细胞/I型干扰素(pDCs/IFN-I)途径诱导多种组织脏器（尤其是肠道）天然淋巴细胞（innate lymphoid cells，ILCs）凋亡，删除pDCs或阻断IFN-I可明显抑制ILCs凋亡并恢复其功能，进而减轻肠道粘膜损伤；在HIV-1感染病人和人源化小鼠模型中，发现骨髓造血干细胞（hematopoietic stem cells，HSCs）增殖和分化能力显著下降；而删除pDCs可显著恢复HSCs增殖和分化能力、纠正HIV-1诱导的HSCs基因异常表达。鉴定了CD4+ ILC1s新亚群，并发现它是HIV-1储藏库细胞，为消除HIV-1储藏库，实现其功能性治愈提出了新的治疗靶点。.综上所述我们的主要科学发现为：HIV-1感染可激活 pDCs/IFN-I 通路并诱导ILCs凋亡和造血干细胞功能损伤，最终损伤机体抗病毒免疫能力、建立慢性感染。阐明了病毒感染诱导免疫细胞凋亡（数量减少）和功能衰竭（质量下降）的机制。至此我们提出了这样的学术观点：pDCs/IFN-I通路激活是HIV-1感染引起肠道免疫屏障和骨髓造血能力损伤的关键“扳机点”，体内删除pDCs或阻断IFN-I是恢复上述重要脏器免疫功能的新策略。

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