Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
J Immunol. 2012 Jul 15;189(2):885-96. doi: 10.4049/jimmunol.1200681. Epub 2012 Jun 11.
Microbial translocation has been linked to systemic immune activation in HIV-1 disease, yet mechanisms by which microbes may contribute to HIV-associated intestinal pathogenesis are poorly understood. Importantly, our understanding of the impact of translocating commensal intestinal bacteria on mucosal-associated T cell responses in the context of ongoing viral replication that occurs early in HIV-1 infection is limited. We previously identified commensal Escherichia coli-reactive Th1 and Th17 cells in normal human intestinal lamina propria (LP). In this article, we established an ex vivo assay to investigate the interactions between Th cell subsets in primary human LP mononuclear cells (LPMCs), commensal E. coli, and CCR5-tropic HIV-1(Bal). Addition of heat-killed E. coli to HIV-1-exposed LPMCs resulted in increases in HIV-1 replication, CD4 T cell activation and infection, and IL-17 and IFN-γ production. Conversely, purified LPS derived from commensal E. coli did not enhance CD4 T cell infection. E. coli exposure induced greater proliferation of LPMC Th17 than Th1 cells. Th17 cells were more permissive to infection than Th1 cells in HIV-1-exposed LPMC cultures, and Th17 cell infection frequencies significantly increased in the presence of E. coli. The E. coli-associated enhancement of infection was dependent on the presence of CD11c(+) LP dendritic cells and, in part, on MHC class II-restricted Ag presentation. These results highlight a potential role for translocating microbes in impacting mucosal HIV-1 pathogenesis during early infection by increasing HIV-1 replication and infection of intestinal Th1 and Th17 cells.
微生物易位与 HIV-1 疾病中的系统性免疫激活有关，但微生物如何促进与 HIV 相关的肠道发病机制的机制尚不清楚。重要的是，我们对于易位共生肠道细菌在 HIV-1 感染早期发生的持续病毒复制背景下对黏膜相关 T 细胞反应的影响的理解是有限的。我们之前在正常人类肠道固有层（LP）中鉴定了共生大肠杆菌反应性 Th1 和 Th17 细胞。在本文中，我们建立了一种体外测定法来研究原发性人 LP 单核细胞（LPMCs）、共生大肠杆菌和 CCR5 嗜性 HIV-1（Bal）中 Th 细胞亚群之间的相互作用。将热灭活的大肠杆菌添加到 HIV-1 暴露的 LPMCs 中会导致 HIV-1 复制、CD4 T 细胞激活和感染以及 IL-17 和 IFN-γ 产生增加。相反，源自共生大肠杆菌的纯化 LPS 不会增强 CD4 T 细胞感染。大肠杆菌暴露诱导 LPMC Th17 比 Th1 细胞更多地增殖。在 HIV-1 暴露的 LPMC 培养物中，Th17 细胞比 Th1 细胞更容易感染，并且在大肠杆菌存在的情况下，Th17 细胞感染频率显着增加。大肠杆菌相关感染增强取决于 CD11c（+）LP 树突状细胞的存在，并且部分取决于 MHC 类 II 限制性 Ag 呈递。这些结果强调了易位微生物在通过增加肠道 Th1 和 Th17 细胞的 HIV-1 复制和感染来影响早期感染期间黏膜 HIV-1 发病机制方面的潜在作用。
