TCRαβ+NK1.1-CD4-CD8- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

Dan Tian; Yuhualei Pan; Yushang Zhao; Huan Wang; Yue Tian; Lu Yang; Wen Shi; Chengjie Zhang; Yanbing Zhu; Yongbo Zhang; Songlin Wang; Dong Zhang

doi:10.7150/thno.80307

TCRαβ⁺NK1.1^-CD4^-CD8^- double-negative T cells inhibit central and peripheral inflammation and ameliorate ischemic stroke in mice

Theranostics. 2023 Jan 10;13(3):896-909. doi: 10.7150/thno.80307. eCollection 2023.

Authors

Dan Tian^{1

2

3

4

5}, Yuhualei Pan^{2

3

4

5

6}, Yushang Zhao^{3

4

5

6}, Huan Wang^{3

4

5

6}, Yue Tian^{1

2

3

4

5

6}, Lu Yang^{1

2

3

4

5}, Wen Shi^{2

3

4

5

6}, Chengjie Zhang⁷, Yanbing Zhu^{2

3

4

5

6}, Yongbo Zhang⁷, Songlin Wang^{2

5}, Dong Zhang^{1

2

3

4

5

6

8}

Affiliations

¹ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
² Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
³ Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China.
⁴ National Clinical Research Center for Digestive Diseases, Beijing, China.
⁵ Beijing Laboratory of Oral Health, Capital Medical University School of Stomatology, Beijing, China.
⁶ Beijing Clinical Research Institute, Beijing, China.
⁷ Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
⁸ Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China.

Abstract

Background: Excessive immune activation leads to secondary injury and impedes injured brain recovery after ischemic stroke. However, few effective methods are currently used for equilibrating immune balance. CD3⁺NK1.1^-TCRβ⁺CD4^-CD8^- double-negative T (DNT) cells which do not express NK cell surface markers are unique regulatory cells that maintain homeostasis in several immune-related diseases. However, the therapeutic potential and regulatory mechanism of DNT cells in ischemic stroke are still unknown. Methods: Mouse ischemic stroke is induced by occlusion of the distal branches of the middle cerebral artery (dMCAO). DNT cells were adoptively transferred intravenously into ischemic stroke mice. Neural recovery was evaluated by TTC staining and behavioral analysis. Using immunofluorescence, flow cytometry, and RNA sequencing, the immune regulatory function of DNT cells was investigated at different time points post ischemic stroke. Results: Adoptive transfer of DNT cells significantly reduces infarct volume and improves sensorimotor function after ischemic stroke. DNT cells suppress peripheral Trem1⁺ myeloid cell differentiation during the acute phase. Furthermore, they infiltrate the ischemic tissue via CCR5 and equilibrate the local immune balance during the subacute phase. During the chronic phase, DNT cells enhance Treg cell recruitment through CCL5, eventually developing an immune homeostatic milieu for neuronal recovery. Conclusions: DNT cell treatment renders the comprehensive anti-inflammatory roles in specific phases of ischemic stroke. Our study suggests that the adoptive transfer of regulatory DNT cells may be a potential cell-based therapy for ischemic stroke.

Keywords: Double-negative T cell; Ischemic stroke; Myeloid cell; Regulatory T cell.

Publication types

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

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Inflammation
Ischemic Stroke* / therapy
Mice
Receptors, Antigen, T-Cell, alpha-beta
T-Lymphocytes, Regulatory

Substances

Receptors, Antigen, T-Cell, alpha-beta