Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Abstract

Key Points• Regulatory T cells are promoters of ischemic stroke by inducing dysfunction of the cerebral microvasculature. We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic antiinflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in IntroductionIschemic stroke induces a profound local inflammatory response involving various types of immune cells that transmigrate across the activated blood-brain barrier to invade the brain in a timed fashion. 1 Although previous research mainly focused on the role of innate immune cells, 2 recent evidence suggests that T cells, which belong to the adaptive immune system, also contribute critically to stroke development, especially in the early phase. 3 T cells have been identified in the postischemic brain as soon as 24 hours after reperfusion, 4 and Abs directed against vascular adhesion receptors expressed on the brain endothelium or leukocyte very late antigen-4 (VLA-4) expressed on lymphocytes inhibited T-cell transmigration and reduced tissue damage in models of stroke. 5 We and others showed recently that recombination activating gene (Rag1)-deficient mice, which lack functional T cells, are largely resistant against ischemic neurodegeneration. 6-8 T cellmediated brain damage became manifest by 24 hours after transient middle cerebral artery occlusion (tMCAO) and did not depend on antigen recognition or costimulation. 8 This clearly argues against TCR-driven mechanisms of tissue damage and suggests instead that T cells act detrimentally in ischemic stroke through antigenindependent pathways, at least during the early phase. Moreover, Rag1 Ϫ/Ϫ mice did not display a gross defect in thrombus formation after artificial vessel wall injury, which could easily explain the stroke protective phenotype in these animals. 8 Although the deleterious effects of T cells in stroke pathophysiology are well accepted, the functional relevance of the different T-cell subsets for stroke progression is less clear, as is their pathologic contribution at the different stages of cerebral ischemia (ie, acute versus chronic). Using adoptive cell transfer in Rag1 Ϫ/Ϫ mice, we could demonstrate that natural killer T cells (NKT cells) Submitted April 26, 2012; accepted October 27, 2012.Prepublished online as Blood First Edition paper, November 15, 2012; DOI 10.1182/blood-2012-04-426734. *C.K. and P.K. ...

Immune Cell Infiltration in Malignant Middle Cerebral Artery Infarction: Comparison with Transient Cerebral Ischemia

“…32 We found no increase in CD4 þ CD25 þ T cells, which includes activated CD4 þ T cells and Tregs, at 3 hours after pMCAO, but a marked increase in these cells in the ischemic hemisphere 24 hours after either pMCAO or tMCAO. A 10-fold increase in Treg cells was recently reported at 14 days after tMCAO.…”

Platelets induce apoptosis via membrane-bound FasL

“…For PLT depletion, PLT-depleting serum (10 mL in PBS, IP) or control serum was applied 24 hours before tMCAO. 42 For depletion of macrophages, clodronate liposomes or control liposomes were injected into mice as described before. 37 Furthermore, in some experiments, GPIIb-IIIa was inhibited to prevent intravascular thrombosis by injection of 100 mg anti-GPIIb-IIIa F(ab) 2 or control IgG as described before.…”

Antigen Presentation After Stroke

“…While Treg conferred neuroprotection in certain experimental stroke models [63], they did not seem to affect the neurological outcome in other studies [64]. Furthermore, some studies highlighted the deleterious function of Tregs in acute stroke by inducing dysfunction of the cerebral microvasculature [71], also after Treg boosting with CD28 superagonist [72]. However in other studies, a neuroprotective role of Tregs was observed when these cells were expanded with CD28 superagonist [73], after inhibiting histone deacetylases [74], or after Treg adoptive transfer [74][75][76].…”