INSERM, UMR1043, Toulouse, France.
aPresent affiliation: Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
J Infect Dis. 2019 Jul 31;220(5):830-840. doi: 10.1093/infdis/jiz123.
The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)-infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1-infected individuals.
尽管持续进行抗逆转录病毒治疗（ART），但大多数人类免疫缺陷病毒 1 型（HIV-1）感染者的肠道黏膜中 CD4+T 细胞（尤其是辅助性 T 细胞 17 型[Th17]细胞）的恢复仍不完全。在此，我们报告在接受 ART 期间十二指肠黏膜中 CXCR3+T 细胞的绝对数量增加。Th1 和 CXCR3+CD8+T 细胞的频率增加，与黏膜中 CCL20 和 CCL25 的表达呈负相关。在离体分析中，我们表明 Th1 和效应性 CD8+T 细胞产生的主要细胞因子干扰素 γ下调小肠上皮细胞中 CCL20 和 CCL25 的表达，同时增加 CXCR3 的配体 CXCL9/10/11 的表达。肠上皮细胞产生的促 Th1 细胞因子白细胞介素 18 也有助于下调 CCL20 的表达，并增加 Th1 细胞中干扰素 γ的产生。这可能会使 CXCR3 驱动的 Th1 和效应性 CD8+T 细胞募集到肠道的放大循环持续存在，同时损害 CCR6-CCL20 轴介导的 Th17 细胞归巢，而在接受治疗的 HIV-1 感染者中。
