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1、Regulatory T cells are key cerebroprotective immunomodulators in acute experimental strokeNature Medicine, 2009; 15 (2):192199Reporter: Xiao-Qing TangIntroduction1. Inflammatory and Brain IschemiaUpregulation of cerebral proinflammatory cytokines, activation of local microglia and systemic lymphocyt
2、es and invasion of leukocytes in the brain contribute substantially to ischemic brain damage. 2.The new strategy of cerebroprotection ：immunomodulator (-) Proinflammatory cytokines: TNF-, INF- and IL-1 (+)Anti-inflammatory cytokines: IL-10 and TGF-3.Endogenous counterregulatory immune mechanismsTreg
3、 cells: CD4+CD25+ forkhead box P3 (Foxp3)+ regulatory T lymphocytes Play a key part in controlling immune responses under physiological conditions and in various systemic and central nervous system inflammatory diseases. Alter the activity of antigen-presenting cells Secrete anti-inflammatory molecu
4、les, including IL-10 and TGF- IL-10 has a beneficial effect in cerebral ischemia; Treg cells show relative resistance to cerebral ischemia.Previous studies have reported that:Objectives:1. Characterize the profound impact of endogenous Treg cells on outcome after ischemic stroke;2. Identify their ce
5、llular targets and protective signaling pathways.Question:What is the functional role of Treg cells in cerebral ischemia?Results1. Regulatory T cells are cerebroprotective after brain ischemia2. Treg cell depletion elevates brain cytokine expression3. Proinflammatory cytokine antagonization reduces
6、brain damage4. Treg cell depletion alters cerebral leukocyte invasion5. Treg cells suppress enhanced systemic cytokine expression6. IL-10 is the main mediator of the Treg cell cerebroprotective effect1. Regulatory T cells are cerebroprotective after brain ischemia1.1 Infarcts enlarged significantly
7、at 7 d, in Treg cell-depleted miceThe injection of antibodies to CD25 resulted in depletion of at least half of the Foxp3+ cells and a 90% reduction of CD25+ cells in lymphatic tissue but did not affect other leukocytes .Permanent MCAO model1.2 Treg celldepleted mice had a significantly worsened fun
8、ctional outcomeFunctional neurological deficit was assessed by asymmetry test the corner testPermanent MCAO modelTreg cell depletion augment 30-min transient filament-MCAO induced extensive ischemic lesions, but not 90-min transient filament-MCAO.1.3 Treg cell depletion Exacerbated Infarct volume in
9、 reversible filament-induced MCAO model 1.4 Rag2-/- mice receiving CD4+CD25- cells showed markedly larger infarcts Either CD4+ cells (including CD4+CD25+ Treg cells; control), purified Treg cells or CD4+CD25- cells were transferred into Rag2-/- mice 7 d before permanent MCAO, and infarct sizes were
10、determined 7 d after MCAO.The Rag2-/- mouse lacks all B and T cell function as a result of homozygous deletion of the Recombinase Activating Gene 2 (Rag2). Summary 1Treg cell depletion exacerbated infarct volume in MCAO model Regulatory T cells are cerebroprotective after brain ischemia2. Treg cell
11、depletion elevates brain cytokine expression2.1 TNF-, INF- and IL-1 expression was substantially upregulated after ischemia in Treg cell- depleted mice 2.2 Treg cell depletion had a comparatively minor effect on postischemic cerebral expression of the anti-inflammatory cytokines IL-10 and TGF-Treg c
12、ell depletion elevates brain Proinflammatory cytokine expression: TNF-, INF- and IL-1Summary 2Regulatory T cells down-regulate Proinflammatory cytokine expression3. Proinflammatory cytokine antagonization reduces brain damage3.1 Early antagonization of TNF- and later antagonization of IFN- produced
13、a significant infarct reduction . Early antagonization of TNF-, but not IFN-, 15 min after MCAO significantly reduced infarct size. In contrast, injection of the antibodies 3 d after MCAO produced an inverse efficacy pattern, with significant infarct reduction only after i.c.v. IFN- antagonization.3
14、.2 Early TNF- and late IFN- antagonization significantly prevented secondary infarct growth in Treg celldepleted mice3.3 Increased IFN- expression in Treg cell-depleted mice 3 d after MCAO was significantly reduced by TNF- neutralization or combined with IL-1 neutralization 15 min after MCAOTNF- and
15、 IL-1 play an important role in the delayed induction of overshooting IFN- productionInhibition of Proinflammatory cytokine reduces brain damageSummary 3Regulatory T cells down-regulate Proinflammatory cytokine expressionRegulatory T cells prevented brain ischemia by down-regulating proinflammatory
16、cytokine, such as TNF-, INF- and IL-1 4.1 Myeloperoxidase-positive cells were predominantly detected in the ischemic core and the peri-infarct region4. Treg cell depletion alters cerebral leukocyte invasion24 h after MCAO myeloperoxidase-positive (MPO+) neutrophilic granulocytes predominantly located in the necrotic area and the border of the ischemic zone4.2 Treg cell depletion altered neutrophil invasion in the infarcted hemisphere at
