Regulatory T cells in ischemic stroke

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Abstract

The pathophysiological mechanisms of neuroinflammation, angiogenesis, and neuroplasticity are currently the hotspots of researches in ischemic stroke. Regulatory T cells (Tregs), a subset of T cells that control inflammatory and immune responses in the body, are closely related to the pathogenesis of ischemic stroke. They participate in the inflammatory response and neuroplasticity process of ischemic stroke by various mechanisms, such as secretion of anti‐inflammatory factors, inhibition of pro‐inflammatory factors, induction of cell lysis, production of the factors that promote neural regeneration, and modulation of microglial and macrophage polarization. However, it remains unclear whether Tregs play a beneficial or deleterious role in ischemic stroke and the effect of Tregs in different stages of ischemic stroke. Here, we discuss the dynamic changes of Tregs at various stages of experimental and clinical stroke, the potential mechanisms under Tregs in regulating stroke and the preclinical studies of Tregs‐related treatments, in order to provide a reference for clinical treatment.

Abstract

This review is more comprehensive and specific summarizes the dynamic changes and potential mechanisms of Tregs in the peripheral and brain after ischemic stroke, and Tregs‐related treatments in stroke. To help researchers gain an overall understanding of Tregs in stroke.

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Most cited references 97

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Control of regulatory T cell development by the transcription factor Foxp3.

Shohei Hori, Takashi Nomura, Shimon Sakaguchi (2003)

Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells. Furthermore, retroviral gene transfer of Foxp3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+ regulatory T cells. Thus, Foxp3 is a key regulatory gene for the development of regulatory T cells.

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Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

S. Sakaguchi, N Sakaguchi, M Asano … (1995)

Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.

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Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.

Mathias Gelderblom, Frank Leypoldt, Karin Steinbach … (2009)

Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model. Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets. Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere. This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.

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Author and article information

Contributors

Xiangjian Zhang:

ORCID: https://orcid.org/0000-0003-0114-1668

zhang6xj@aliyun.com

Journal

Journal ID (nlm-ta): CNS Neurosci Ther

Journal ID (iso-abbrev): CNS Neurosci Ther

Journal ID (doi): 10.1111/(ISSN)1755-5949

Journal ID (publisher-id): CNS

Title: CNS Neuroscience & Therapeutics

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1755-5930

ISSN (Electronic): 1755-5949

Publication date (Electronic): 20 January 2021

Publication date Collection: June 2021

Volume: 27

Issue: 6 ( doiID: 10.1111/cns.v27.6 )

Pages: 643-651

Affiliations

[ ¹ ] Department of Neurology Second Hospital of Hebei Medical University Shijiazhuang Hebei PR China

[ ² ] Hebei Collaborative Innovation Center for Cardio‐cerebrovascular Disease Shijiazhuang Hebei PR China

[ ³ ] Hebei Vascular Homeostasis Key Laboratory Shijiazhuang Hebei PR China

Author notes

[*] [* ] Correspondence

Xiangjian Zhang, Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.

Email: zhang6xj@ 123456aliyun.com

Author information

Xiangjian Zhang https://orcid.org/0000-0003-0114-1668

Article

Publisher ID: CNS13611

DOI: 10.1111/cns.13611

PMC ID: 8111493

PubMed ID: 33470530

SO-VID: 6c4f1461-96cd-4b32-b15c-293bc45092c6

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 28 December 2020

Date received : 19 September 2020

Date accepted : 30 December 2020

Page count

Figures: 2, Tables: 0, Pages: 9, Words: 7125

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source-schema-version-number 2.0

cover-date June 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:11.05.2021

ScienceOpen disciplines: Neurosciences

Keywords: immunomodulation,ischemic stroke,neuroinflammation,neuroplasticity,regulatory t cells

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: immunomodulation, ischemic stroke, neuroinflammation, neuroplasticity, regulatory t cells

Regulatory T cells in ischemic stroke

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Regulatory T cell (Treg) therapy

Most cited references 97

Control of regulatory T cell development by the transcription factor Foxp3.

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.

Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.

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