During Mycobacterium tuberculosis (Mtb) infection, mice lacking the IL-27R exhibit lower bacterial burdens but develop an immunopathological sequelae in comparison to wild-type mice. We here show that this phenotype correlates with an enhanced recruitment of antigen-specific CCR6⁺ CD4⁺ T cells and an increased frequency of IL-17A-producing CD4⁺ T cells. By comparing the outcome of Mtb infection in C57BL/6, IL-27R-deficient and IL-27R/IL-17A-double deficient mice, we observed that both the increased protection and elevated immunopathology are supported by IL-17A. Whereas IL-17A neither impacts the development of Tr1 cells nor the expression of PD1 and KLRG1 on T cells in IL-27R-deficient mice during infection, it regulates the presence of multifunctional T-cells in the lungs, co-expressing IFN-γ, IL-2 and TNF. Eventually, IL-17A supports Cxcl9, Cxcl10 and Cxcl13 expression and the granulomatous response in the lungs of infected IL-27R-deficient mice. Taken together, IL-17A contributes to protection in Mtb-infected IL-27R-deficient mice probably through a chemokine-mediated recruitment and strategic positioning of multifunctional T cells in granulomas. As IL-27 limits optimal antimycobacterial protection by inhibiting IL-17A production, blocking of IL-27R-mediated signaling may represent a strategy for improving vaccination and host-directed therapy in tuberculosis. However, because IL-27 also prevents IL-17A-mediated immunopathology, such intervention has to be tightly controlled.

中文翻译：

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IL-17A 支持结核分枝杆菌感染的 IL-27R-α 缺陷小鼠的保护作用和病理学增强，并且与 IL-17A 诱导的多功能 T 细胞扩增有关。

在结核分枝杆菌 (Mtb) 感染期间，缺乏 IL-27R 的小鼠表现出较低的细菌负荷，但与野生型小鼠相比会出现免疫病理学后遗症。我们在这里表明，这种表型与抗原特异性 CCR6 ⁺ CD4 ⁺ T 细胞的增强募集和产生 IL-17A 的 CD4 ^{+的频率增加相关}T 细胞。通过比较 C57BL/6、IL-27R 缺陷和 IL-27R/IL-17A 双缺陷小鼠中 Mtb 感染的结果，我们观察到 IL-17A 支持增强的保护和升高的免疫病理学。尽管 IL-17A 既不影响 Tr1 细胞的发育，也不影响感染期间 IL-27R 缺陷小鼠 T 细胞上 PD1 和 KLRG1 的表达，它调节肺部多功能 T 细胞的存在，共表达 IFN-γ 、IL-2 和 TNF。最终，IL-17A 支持 Cxcl9、Cxcl10 和 Cxcl13 表达以及受感染的 IL-27R 缺陷小鼠肺部的肉芽肿反应。总之，IL-17A 可能通过趋化因子介导的募集和多功能 T 细胞在肉芽肿中的战略定位，有助于保护 Mtb 感染的 IL-27R 缺陷小鼠。由于 IL-27 通过抑制 IL-17A 的产生限制了最佳的抗分枝杆菌保护，因此阻断 IL-27R 介导的信号可能代表了一种改善结核病疫苗接种和宿主定向治疗的策略。然而，由于 IL-27 还可以阻止 IL-17A 介导的免疫病理学，因此必须严格控制这种干预。