Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke

被引：267

作者：

Shi, Ligen ^{[1
,2
]}

Sun, Zeyu ^{[1
,2
]}

Su, Wei ^{[1
,2
]}

Xu, Fei ^{[1
,2
,3
]}

Xie, Di ^{[1
,2
]}

Zhang, Qingxiu ^{[1
,2
]}

Dai, Xuejiao ^{[1
,2
]}

Iyer, Kartik ^{[1
,2
]}

Hitchens, T. Kevin ^{[4
,5
]}

Foley, Lesley M. ^{[4
,5
]}

Li, Sicheng ^{[1
,2
]}

Stolz, Donna B. ^{[6
]}

Chen, Kong ^{[7
]}

Ding, Ying ^{[8
]}

Thomson, Angus W. ^{[9
,10
]}

Leak, Rehana K. ^{[1
,2
,11
]}

Chen, Jun ^{[1
,2
,3
]}

Hu, Xiaoming ^{[1
,2
,3
]}

机构：

[1] Univ Pittsburgh, Sch Med, Pittsburgh Inst Brain Disorders & Recovery, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA

[3] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA

[4] Univ Pittsburgh, Anim Imaging Ctr, Pittsburgh, PA 15203 USA

[5] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15203 USA

[6] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA 15213 USA

[7] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA

[8] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15213 USA

[9] Univ Pittsburgh, Starzl Transplantat Inst, Dept Surg, Sch Med, Pittsburgh, PA 15213 USA

[10] Univ Pittsburgh, Dept Immunol, Sch Med, Pittsburgh, PA 15213 USA

[11] Duquesne Univ, Grad Sch Pharmaceut Sci, Pittsburgh, PA 15282 USA

来源：

IMMUNITY | 2021年 / 54卷 / 07期

关键词：

REGULATORY T-CELLS; FUNCTIONAL RECOVERY; MICE; LYMPHOCYTES; EXPRESSION; THERAPY; DIFFERENTIATION; CORRELATE; PROTECTS; MYELIN;

D O I：

10.1016/j.immuni.2021.04.022

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.

引用

页码：1527 / +

页数：24

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