scholarly journals Regulatory T-cells inhibit microglia-induced pain hypersensitivity in female mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Julia Kuhn ◽  
Ilia D Vainchtein ◽  
Joao M Braz ◽  
Katherine Hamel ◽  
Mollie Bernstein ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Microglial Activation ◽  
Transcriptional Profiling ◽  
Intrathecal Administration ◽  
Pain Hypersensitivity ◽  
Female Mice ◽  
Stimulating Factor

Peripheral nerve injury-induced neuropathic pain is a chronic and debilitating condition characterized by mechanical hypersensitivity. We previously identified microglial activation via release of colony stimulating factor 1 (CSF1) from injured sensory neurons as a mechanism contributing to nerve injury-induced pain. Here we show that intrathecal administration of CSF1, even in the absence of injury, is sufficient to induce pain behavior, but only in male mice. Transcriptional profiling and morphologic analyses after intrathecal CSF1 showed robust immune activation in male but not female microglia. CSF1 also induced marked expansion of lymphocytes within the spinal cord meninges, with preferential expansion of regulatory T-cells (Tregs) in female mice. Consistent with the hypothesis that Tregs actively suppress microglial activation in females, Treg deficient (Foxp3DTR) female mice showed increased CSF1-induced microglial activation and pain hypersensitivity equivalent to males. We conclude that sexual dimorphism in the contribution of microglia to pain results from Treg-mediated suppression of microglial activation and pain hypersensitivity in female mice.

Neuroprotective Effects of Ex Vivo Expanded Regulatory T Cells on Trimethyltin Induced Neurodegeneration in Mice

2021 ◽  
Author(s):  
Seon-Young Park ◽  
HyeJin Yang ◽  
Minsook Ye ◽  
Xiao Liu ◽  
Insop Shim ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Adoptive Transfer ◽  
Calcium Binding ◽  
Microglial Activation ◽  
Time Lapse ◽  
Inhibitory Effects ◽  
Immune Balance ◽  
Hippocampal Neurodegeneration

Abstract BackgroundTrimethyltin (TMT) is a potent neurotoxicant that leads to hippocampal neurodegeneration. Regulatory T cells (Tregs) play an important role in maintaining the immune balance in the central nervous system (CNS), but their activities are impaired in neurodegenerative diseases. In this study, we aimed to determine whether adoptive transfer of Tregs, as a living drug, ameliorates hippocampal neurodegeneration in TMT-intoxicated mice.MethodsCD4+CD25+ Tregs were expanded in vitro and adoptively transferred to TMT-treated mice. First, we explored the effects of Tregs on behavioral deficits using the Morris water maze and elevated plus maze tests. Biomarkers related to memory formation, such as cAMP response element-binding protein (CREB), protein kinase C (PKC), neuronal nuclear protein (NeuN), nerve growth factor (NGF), and ionized calcium binding adaptor molecule 1 (Iba1) in the hippocampus were examined by immunohistochemistry after mouse sacrifice. To investigate the neuroinflammatory responses, the polarization status of microglia was examined in vivo and in vitro using real-time reverse transcription polymerase chain reaction (rtPCR) and Enzyme-linked immunosorbent assy (ELISA). Additionally, the inhibitory effects of Tregs on TMT-induced microglial activation were examined using time-lapse live imaging in vitro with an activation-specific fluorescence probe, CDr20.ResultsAdoptive transfer of Tregs improved spatial learning and memory functions and reduced anxiety in TMT-intoxicated mice. Additionally, adoptive transfer of Tregs reduced neuronal loss and recovered the expression of neurogenesis enhancing molecules in the hippocampi of TMT-intoxicated mice. In particular, Tregs inhibited microglial activation and pro-inflammatory cytokine release in the hippocampi of TMT-intoxicated mice. The inhibitory effects of TMT were also confirmed via in vitro live time lapse imaging in a Treg/microglia co-culture system.ConclusionsThese data suggest that adoptive transfer of Tregs ameliorates disease progression in TMT-induced neurodegeneration by promoting neurogenesis and modulating microglial activation and polarization.

Regulatory T cells counteract neuropathic pain through inhibition of the Th1 response at the site of peripheral nerve injury

Pain ◽  
2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Marcela Davoli-Ferreira ◽  
Kalil A. de Lima ◽  
Miriam M. Fonseca ◽  
Rafaela M. Guimarães ◽  
Francisco I. Gomes ◽  
...  
Keyword(s):  
T Cells ◽  
Neuropathic Pain ◽  
Regulatory T Cells ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Th1 Response

Abstract 113: Regulatory T Cells Contribute to Sexual Dimorphic Outcomes After Acute Ischemic Brain Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zeyu Sun ◽  
Wei Su ◽  
Ligen Shi ◽  
Jie Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Infarct Volume ◽  
Young Male ◽  
Young Female ◽  
Male Mice ◽  
Stroke Outcomes ◽  
Female Mice ◽  
Ifn Γ

Introduction: The contribution of CD4 + Foxp3 + regulatory T cells (Treg) to acute stroke outcomes has been controversially reported in young male murine models of stroke, their effects in female stroke mice, however, are not characterized. This study explored the sexual dimorphisms in Treg and its contribution to acute stroke outcomes. Methods: Cerebral ischemia was induced by 60 min tMCAO in male or female (Young: 10-week, aged: 15-month) wild type (WT) mice and DTR mice expressing the diphtheria toxin (DT) receptor under the control of Foxp3 promoter. Tregs depletion was achieved by DT injection in DTR mice for 3 days prior to tMCAO. Infarct volume, sensorimotor functions and peripheral immune cell populations were assessed up to 5d after stroke. For RNA sequencing analysis, Tregs were sorted from blood of male or female DTR mice at 5d after sham or tMCAO surgery. Results: Young Treg competent (WT mice or DTR mice without DT) female mice exhibited significantly reduced infarct volume, as assessed by MRI T2 scanning and MAP2 staining, and greatly improved sensorimotor functions (rotarod test and adhesive removal test) compared to age- and genotype-matched male mice (n=8/group) 5d after tMCAO. Treg depletion deprived the neuroprotection in young female, while showed no significant effect on young male or aged female mice (n=8/group). RNA-seq analysis showed that IFN-γ signaling was downregulated in female Treg while upregulated in male Treg, suggesting a sexual difference in Treg-mediated immune response after stroke. Flow cytometry revealed ameliorated immune cell activation in blood and brain in female vs male mice 5d after stroke. Furthermore, Treg were isolated from young female, young male, aged female or female mice subjected to ovariectomy, and adoptively transferred (1 million cell/animal, iv) to young male mice 1 hour after tMCAO. Only young female Treg significantly reduced the infarct volume and improved sensorimotor functions compared to other treatment groups (n=7-8/group). Conclusion: Treg contribute to the neuroprotection in young female vs male in an age- and hormone-dependent manner. Transcriptomic analysis uncovered sexual differences in an IFN-γ centered regulatory pathways in Tregs, which keep post-stroke immune responses in check.

scholarly journals Granulocyte macrophage colony-stimulating factor treatment of a patient in myasthenic crisis: Effects on regulatory T cells

2012 ◽  
Vol 46 (3) ◽  
pp. 449-453 ◽  
Author(s):  
Julie Rowin ◽  
Muthusamy Thiruppathi ◽  
Ebinehita Arhebamen ◽  
Jianrong Sheng ◽  
Bellur S. Prabhakar ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Myasthenic Crisis ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor
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