Lu Chun-Hao, Ma Jason, Lin Ming-Chieh, Wu Cheng-Jang, Kuo Chieh-Ying, Chiang-Ni Chuan, Kuo Ming-Ling
Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan, Taiwan.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Med Microbiol Immunol. 2025 May 22;214(1):25. doi: 10.1007/s00430-025-00835-1.
Bacterial superantigens are potent immune activators that trigger T cell proliferation and intensive release of cytokines, leading to toxic shock syndrome. Also, they impair host immune responses, increasing bacterial carriage and transmission. Several studies proposed that superantigens can induce regulatory T (Treg) cells, which may suppress immune responses against bacterial infection. However, the mechanism of Treg cell induction by superantigens is still elusive. We here demonstrated that streptococcal pyrogenic exotoxin A (SPEA) promoted human CD4CD25Foxp3 T cell induction in a dose- and time-dependent manner and the induction required antigen-presenting cells (APCs). SPEA-induced CD4CD25 T cells could suppress allogeneic T cell proliferation and IL-2 secretion. Flow cytometric analyses demonstrated high expression of TNFR2 on SPEA-induced CD4CD25Foxp3 T cells. Blocking the interaction between TNF-⍺ and TNFR2 reduced SPEA-induced CD25Foxp3 Treg cells. Our present study suggests a mechanism that the TNF-⍺ and TNFR2 axis is required for the induction of human CD4CD25Foxp3 Treg cells by SPEA, which implicates a potential strategy to enhance the clearance of Group A streptococcus infection through reducing Treg cell induction by the inhibition of TNFR2 signaling.
细菌超抗原是强效免疫激活剂，可触发T细胞增殖并大量释放细胞因子，导致中毒性休克综合征。此外，它们会损害宿主免疫反应，增加细菌携带和传播。多项研究表明，超抗原可诱导调节性T（Treg）细胞，后者可能会抑制针对细菌感染的免疫反应。然而，超抗原诱导Treg细胞的机制仍不清楚。我们在此证明，化脓性链球菌致热外毒素A（SPEA）以剂量和时间依赖性方式促进人CD4CD25Foxp3 T细胞的诱导，且该诱导需要抗原呈递细胞（APC）。SPEA诱导的CD4CD25 T细胞可抑制同种异体T细胞增殖和IL-2分泌。流式细胞术分析表明，TNFR2在SPEA诱导的CD4CD25Foxp3 T细胞上高表达。阻断TNF-α与TNFR2之间的相互作用可减少SPEA诱导的CD25Foxp3 Treg细胞。我们目前的研究提示了一种机制，即TNF-α和TNFR2轴是SPEA诱导人CD4CD25Foxp3 Treg细胞所必需的，这暗示了一种潜在策略，即通过抑制TNFR2信号传导减少Treg细胞诱导，从而增强A组链球菌感染的清除。
