Double-negative T cells remarkably promote neuroinflammation after ischemic stroke

Hailan Meng; Haoran Zhao; Xiang Cao; Junwei Hao; He Zhang; Yi Liu; Min-Sheng Zhu; Lizhen Fan; Leihua Weng; Lai Qian; Xiaoying Wang; Yun Xu

doi:10.1073/pnas.1814394116

Double-negative T cells remarkably promote neuroinflammation after ischemic stroke

Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5558-5563. doi: 10.1073/pnas.1814394116. Epub 2019 Feb 28.

Authors

Hailan Meng^{1

2

3

4

5}, Haoran Zhao^{1

2}, Xiang Cao^{1

2

3

4

5}, Junwei Hao⁶, He Zhang^{1

2

3

4

5}, Yi Liu^{1

2

3

4

5}, Min-Sheng Zhu^{7

8}, Lizhen Fan^{1

2}, Leihua Weng^{1

2}, Lai Qian^{1

2

3

4

5}, Xiaoying Wang⁹, Yun Xu^{10

2

3

4

5}

Affiliations

¹ Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210008 Nanjing, China.
² Institute of Brain Sciences, Nanjing University, 210008 Nanjing, China.
³ Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, 210008 Nanjing, China.
⁴ Jiangsu Province Stroke Center for Diagnosis and Therapy, 210008 Nanjing, China.
⁵ Nanjing Neuropsychiatry Clinic Medical Center, 210008 Nanjing, China.
⁶ Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 300052 Tianjin, China.
⁷ Model Animal Research Center, Nanjing University, 210061 Nanjing, China.
⁸ Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, 210061 Nanjing, China.
⁹ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129.
¹⁰ Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210008 Nanjing, China; xuyun20042001@aliyun.com.

Abstract

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.

Keywords: DNTs; FasL; T cell-mediated immunity; ischemic stroke; neuroinflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged, 80 and over
Animals
Brain / immunology
Brain Ischemia / immunology*
CD3 Complex / immunology*
CD4 Antigens / immunology
CD8 Antigens / immunology
Disease Models, Animal
Female
Humans
Inflammation / immunology
Male
Mice
Mice, Inbred C57BL
Microglia / immunology
Stroke / immunology*
T-Lymphocyte Subsets / immunology*
Tumor Necrosis Factor-alpha / metabolism

Substances

CD3 Complex
CD4 Antigens
CD8 Antigens
Tumor Necrosis Factor-alpha