Double-negative T cells remarkably promote neuroinflammation after ischemic stroke

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 12; pp. 5558 - 5563
• Main Authors: Meng, Hailan, Zhao, Haoran, Cao, Xiang, Hao, Junwei, Zhang, He, Liu, Yi, Zhu, Min-sheng, Fan, Lizhen, Weng, Leihua, Qian, Lai, Wang, Xiaoying, Xu, Yun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.03.2019
• Subjects: Aged, 80 and over; Animals; Biological Sciences; Brain; Brain - immunology; Brain injury; Brain Ischemia - immunology; CD3 antigen; CD3 Complex - immunology; CD4 antigen; CD4 Antigens - immunology; CD8 antigen; CD8 Antigens - immunology; Central nervous system; Disease Models, Animal; FasL protein; Female; Head injuries; Homeostasis; Humans; Immunology; Inflammation; Inflammation - immunology; Ischemia; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Microglia - immunology; Peripheral blood; PTPN2 protein; Signal transduction; Stroke; Stroke - immunology; T-Lymphocyte Subsets - immunology; Time dependence; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; DNTs; FasL; neuroinflammation; T cell-mediated immunity; ischemic stroke
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1814394116

CD3⁺CD4⁻CD8⁻ T cells (double-negative T cells; DNTs) have diverse functions in peripheral immune-related diseases by regulating immunological and inflammatory homeostasis. However, the functions of DNTs in the central nervous system remain unknown. Here, we found that the levels of DNTs were dramatically increased in both the brain and peripheral blood of stroke patients and in a mouse model in a time-dependent manner. The infiltrating DNTs enhanced cerebral immune and inflammatory responses and exacerbated ischemic brain injury by modulating the FasL/PTPN2/TNF-α signaling pathway. Blockade of this pathway limited DNT-mediated neuroinflammation and improved the outcomes of stroke. Our results identified a critical function of DNTs in the ischemic brain, suggesting that this unique population serves as an attractive target for the treatment of ischemic stroke.