Division of Dermatology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Department of Ecology and Evolutionary Biology, UCLA, Los Angeles, California, USA.
J Clin Invest. 2021 Jan 19;131(2). doi: 10.1172/JCI141594.
TH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To elucidate the antimicrobial machinery of the TH17 subset, we studied the response to Cutibacterium acnes, a skin commensal that is resistant to IL-26, the only known TH17-secreted protein with direct antimicrobial activity. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes, which we correlated by RNA sequencing to the expression of transcripts encoding proteins that contribute to antimicrobial activity. Additionally, we validated that AMTH17-mediated killing of C. acnes and bacterial pathogens was dependent on the secretion of granulysin, granzyme B, perforin, and histone H2B. We found that AMTH17 cells can release fibrous structures composed of DNA decorated with histone H2B that entangle C. acnes that we call T cell extracellular traps (TETs). Within acne lesions, H2B and IL-17 colocalized in CD4+ T cells, in proximity to TETs in the extracellular space composed of DNA decorated with H2B. This study identifies a functionally distinct subpopulation of TH17 cells with an ability to form TETs containing secreted antimicrobial proteins that capture and kill bacteria.
TH17 细胞亚群已被定义为有助于炎症和内稳态,但有助于宿主抵御感染的 TH17 细胞的特征尚不清楚。为了阐明 TH17 亚群的抗菌机制,我们研究了对痤疮丙酸杆菌的反应,痤疮丙酸杆菌是一种皮肤共生菌,对 IL-26 具有抗性,而 IL-26 是唯一已知具有直接抗菌活性的 TH17 分泌蛋白。我们生成了具有不同抗痤疮丙酸杆菌活性的痤疮丙酸杆菌特异性抗菌 TH17 克隆(AMTH17),并通过 RNA 测序将其与编码有助于抗菌活性的蛋白的转录本表达相关联。此外,我们验证了 AMTH17 介导的痤疮丙酸杆菌和细菌病原体的杀伤依赖于颗粒酶 B、穿孔素和组蛋白 H2B 的分泌。我们发现 AMTH17 细胞可以释放由带有组蛋白 H2B 的 DNA 装饰的纤维状结构,我们称之为 T 细胞细胞外陷阱(TET),这些结构缠绕着痤疮丙酸杆菌。在痤疮病变中,H2B 和 IL-17 在 CD4+T 细胞中共同定位,与由带有 H2B 的 DNA 组成的细胞外空间中的 TET 接近。这项研究确定了具有形成包含分泌抗菌蛋白的 TET 的能力的 TH17 细胞的一个功能不同的亚群,这些 TET 可以捕获和杀死细菌。