Cancer Exacerbates Ischemic Brain Injury Via Nrp1 (Neuropilin 1)-Mediated Accumulation of Regulatory T Cells Within the Tumor

Background and Purpose: Our previous work documents the transfer of regulatory T cells (Tregs) in rodent models of ischemic stroke protects acute ischemic brain injury by regulating poststroke inflammatory response and thereby ameliorating BBB disruption. However, the low number of Tregs restricts the clinical feasibility of Treg transfer. Recently, in vivo expansion of Tregs with IL-2/IL-2-antibody complex (IL-2/IL-2Ab) was validated protective in autoimmune diseases model,renal ischemia reperfusion model and atherosclerosis. Here we investigate the beneficial effect of IL-2/IL-2Ab on ischemic stroke and decipher the underlying mechanisms. Methods: IL-2/IL-2Ab or isotype IgG was ip injected into C57/BL6 mice for 3 consecutive days. The mice are then subjected to 60-minute middle cerebral artery occlusion (MCAO) or sham operation. Brain infarction, inflammation and neurological performance was assessed up to 7 days after reperfusion. Results: Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ Tregs in the blood, lymph nodes and spleens collected from IL-2/IL-2Ab-treated mice as compared to those from isotype-treated controls. Such Treg elevation could be observed since 3 days after IL-2/IL-2Ab injection and lasts until 7 days after MCAO. Immunochemistry staining confirms the increased number of Foxp3+ cells in the spleen at 3 days after MCAO in IL-2/IL-2Ab-treated mice. IL-2/IL-2Ab promotes function recovery up to 7 days after stroke, as revealed by significantly improved performance in corner test (n=6-9, ***p<0.001), rotarod test (n=8, **p<0.01), cylinder test (n=8, **p<0.01) and adhesive removal test (n=3, *p<0.05). Quantification of TTC staining and microtubule-associated protein (MAP2) staining shows reductions in brain infarct volume at 3 days (n=5-9,*p<0.05) and 7 days (n=7-9,*p<0.01), respectively, after MCAO. Meanwhile, we observed reduced infiltration of peripheral immune cells (CD3+ T cells, MPO+ neutrophils and F4/80+ macrophages) into the ischemic brain. Conclusions: Our finding suggests that IL-2/IL-2Ab treatment is a novel and clinical feasible immune therapy to expand Treg population in vivo, reduce post-stroke inflammatory responses and protect against ischemic brain injury.

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Regulatory T Cells in Ischemic Brain Injury

Springer Series in Translational Stroke Research - Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke ◽

10.1007/978-3-319-32337-4_11 ◽

2016 ◽

pp. 201-215

Author(s):

Arthur Liesz

Keyword(s):

T Cells ◽

Brain Injury ◽

Regulatory T Cells ◽

Ischemic Brain Injury ◽

Ischemic Brain

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Ischemic Brain Injury and Regulatory T Cells

OBM Neurobiology ◽

10.21926/obm.neurobiol.1901023 ◽

2019 ◽

Vol 3 (1) ◽

pp. 1-1

Author(s):

Ito Minako ◽

◽

Srirat Tanakorn ◽

Nakamura Toshihiro ◽

Komai Kyoko ◽

...

Keyword(s):

T Cells ◽

Brain Injury ◽

Regulatory T Cells ◽

Ischemic Brain Injury ◽

Ischemic Brain

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Chronic colitis induces meninges traffic of gut-derived T cells, unbalances M1 and M2 microglia/macrophage and increases ischemic brain injury in mice

Brain Research ◽

10.1016/j.brainres.2018.11.019 ◽

2019 ◽

Vol 1707 ◽

pp. 8-17 ◽

Cited By ~ 7

Author(s):

Yukun Feng ◽

Xiaofei He ◽

Shijian Luo ◽

Xiaofeng Chen ◽

Simei Long ◽

...

Keyword(s):

T Cells ◽

Brain Injury ◽

Ischemic Brain Injury ◽

Chronic Colitis ◽

Ischemic Brain ◽

M2 Microglia

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Non-invasive tracking of CD4+ T cells with a paramagnetic and fluorescent nanoparticle in brain ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15611137 ◽

2015 ◽

Vol 36 (8) ◽

pp. 1464-1476 ◽

Cited By ~ 23

Author(s):

Wei-Na Jin ◽

Xiaoxia Yang ◽

Zhiguo Li ◽

Minshu Li ◽

Samuel Xiang-Yu Shi ◽

...

Keyword(s):

T Cells ◽

Brain Injury ◽

In Vivo Imaging ◽

Inflammatory Diseases ◽

Transfer Model ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Magnetic Resonance Imaging Mri ◽

Infiltrating Lymphocytes

Recent studies have demonstrated that lymphocytes play a key role in ischemic brain injury. However, there is still a lack of viable approaches to non-invasively track infiltrating lymphocytes and reveal their key spatiotemporal events in the inflamed central nervous system (CNS). Here we describe an in vivo imaging approach for sequential monitoring of brain-infiltrating CD4+ T cells in experimental ischemic stroke. We show that magnetic resonance imaging (MRI) or Xenogen imaging combined with labeling of SPIO-Molday ION Rhodamine-B (MIRB) can be used to monitor the dynamics of CD4+ T cells in a passive transfer model. MIRB-labeled CD4+ T cells can be longitudinally visualized in the mouse brain and peripheral organs such as the spleen and liver after cerebral ischemia. Immunostaining of tissue sections showed similar kinetics of MIRB-labeled CD4+ T cells when compared with in vivo observations. Our results demonstrated the use of MIRB coupled with in vivo imaging as a valid method to track CD4+ T cells in ischemic brain injury. This approach will facilitate future investigations to identify the dynamics and key spatiotemporal events for brain-infiltrating lymphocytes in CNS inflammatory diseases.

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