Brain ischemia induces diversified neuroantigen-specific T-Cell responses that exacerbate brain injury

Wei Na Jin, Rayna J Gonzales, Yan Feng, Kristofer Wood, Zhi Chai, Jing Fei Dong, Antonio La Cava, Fu Dong Shi, Qiang Liu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background and Purpose-Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. Methods-Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG 35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigenpresenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. Results-By coupling transfer of labeled MOG 35-55 -specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG 91-108 and MOG 103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. Conclusions-Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.

Original languageEnglish (US)
Pages (from-to)1471-1478
Number of pages8
JournalStroke
Volume49
Issue number6
DOIs
StatePublished - Jan 1 2018

Fingerprint

Brain Ischemia
Brain Injuries
T-Lymphocytes
Autoimmunity
Stroke
Central Nervous System
Middle Cerebral Artery Infarction
Microglia
Antigens
Adoptive Transfer
Brain
Antigen-Presenting Cells
T-Cell Antigen Receptor
Epitopes
Lymphocytes

Keywords

  • adaptive immunity
  • antigen presentation
  • brain injury
  • brain ischemia
  • T-cells

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Brain ischemia induces diversified neuroantigen-specific T-Cell responses that exacerbate brain injury. / Jin, Wei Na; Gonzales, Rayna J; Feng, Yan; Wood, Kristofer; Chai, Zhi; Dong, Jing Fei; La Cava, Antonio; Shi, Fu Dong; Liu, Qiang.

In: Stroke, Vol. 49, No. 6, 01.01.2018, p. 1471-1478.

Research output: Contribution to journalArticle

Jin, WN, Gonzales, RJ, Feng, Y, Wood, K, Chai, Z, Dong, JF, La Cava, A, Shi, FD & Liu, Q 2018, 'Brain ischemia induces diversified neuroantigen-specific T-Cell responses that exacerbate brain injury', Stroke, vol. 49, no. 6, pp. 1471-1478. https://doi.org/10.1161/str.49.suppl
Jin, Wei Na ; Gonzales, Rayna J ; Feng, Yan ; Wood, Kristofer ; Chai, Zhi ; Dong, Jing Fei ; La Cava, Antonio ; Shi, Fu Dong ; Liu, Qiang. / Brain ischemia induces diversified neuroantigen-specific T-Cell responses that exacerbate brain injury. In: Stroke. 2018 ; Vol. 49, No. 6. pp. 1471-1478.
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AU - Jin, Wei Na

AU - Gonzales, Rayna J

AU - Feng, Yan

AU - Wood, Kristofer

AU - Chai, Zhi

AU - Dong, Jing Fei

AU - La Cava, Antonio

AU - Shi, Fu Dong

AU - Liu, Qiang

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N2 - Background and Purpose-Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. Methods-Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG 35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigenpresenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. Results-By coupling transfer of labeled MOG 35-55 -specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG 91-108 and MOG 103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. Conclusions-Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.

AB - Background and Purpose-Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. Methods-Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG 35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigenpresenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. Results-By coupling transfer of labeled MOG 35-55 -specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG 91-108 and MOG 103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. Conclusions-Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.

KW - adaptive immunity

KW - antigen presentation

KW - brain injury

KW - brain ischemia

KW - T-cells

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