Mucosal Th17 Cell Function Is Altered during HIV Infection and Is an Independent Predictor of Systemic Immune Activation
Mucosal Th17 Cell Function Is Altered during HIV Infection and Is an Independent Predictor of Systemic Immune Activation
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DOI：
10.4049/jimmunol.1300829
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发表时间：
2013-09-01
影响因子：
4.4
通讯作者：
Kaul, Rupert
中科院分区：
文献类型：
--
作者：
Kim, Connie J.;McKinnon, Lyle R.;Kaul, Rupert
粘膜Th17细胞通过免疫抑制和促炎功能的微妙平衡，维持肠道上皮屏障，防止管腔细菌的入侵。HIV感染的特征是粘膜Th17耗尽、微生物易位和免疫激活。因此，我们评估了血液和乙状结肠Th17细胞在早期和慢性HIV感染期间的功能，以及短期和长期抗逆转录病毒治疗的影响。Th17细胞被定义为IL-17a(+)的CD4T细胞，并通过共产生炎症细胞因子IL-22、肿瘤坏死因子-α和干扰素-γ以及免疫调节细胞因子IL-10来评估其功能。肠道Th17细胞产生促炎细胞因子的能力比血液中的细胞因子大得多，但从HIV感染的最早阶段起，这种能力就急剧下降。粘膜Th17细胞功能的免疫调节失调，其特征是IL-10/TNF-α比率增加，在HIV感染早期是独一无二的，并与系统免疫活性降低独立相关。抗逆转录病毒治疗迅速恢复了粘膜Th17细胞的数量；然而，粘膜Th17功能、微生物易位和粘膜/系统免疫激活的正常化却延迟了很多。这些发现强调，保护或更快地恢复粘膜Th17功能的策略可能具有重要的治疗益处。
Mucosal Th17 cells maintain the gut epithelial barrier and prevent invasion by luminal bacteria through a delicate balance of immunosuppressive and proinflammatory functions. HIV infection is characterized by mucosal Th17 depletion, microbial translocation, and immune activation. Therefore, we assessed the function of blood and sigmoid Th17 cells during both early and chronic HIV infection, as well as the impact of short- and long-term antiretroviral therapy. Th17 cells were defined as IL-17a(+) CD4 T cells, and their functional capacity was assessed by the coproduction of the inflammatory cytokines IL-22, TNF-alpha, and IFN-gamma, as well as the immunoregulatory cytokine IL-10. Gut Th17 cells had a much greater capacity to produce proinflammatory cytokines than did those from the blood, but this capacity was dramatically reduced from the earliest stages of HIV infection. Immunoregulatory skewing of mucosal Th17 cell function, characterized by an increased IL-10/TNF-alpha ratio, was uniquely seen during early HIV infection and was independently associated with reduced systemic immune activation. Antiretroviral therapy rapidly restored mucosal Th17 cell numbers; however, normalization of mucosal Th17 function, microbial translocation, and mucosal/systemic immune activation was much delayed. These findings emphasize that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefit.