title: Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke.
abstract: Increasing evidences show that immune response affects the reparative mechanisms in injured brain. Recently, we have demonstrated that CD4(+)T cells serve as negative modulators in neurogenesis after stroke, but the mechanistic detail remains unclear. Glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), a multifaceted regulator of immunity belonging to the TNF receptor superfamily, is expressed on activated CD4(+)T cells. Herein, we show, by using a murine model of cortical infarction, that GITR triggering on CD4(+)T cells increases poststroke inflammation and decreases the number of neural stem/progenitor cells induced by ischemia (iNSPCs). CD4(+)GITR(+)T cells were preferentially accumulated at the postischemic cortex, and mice treated with GITR-stimulating antibody augmented poststroke inflammatory responses with enhanced apoptosis of iNSPCs. In contrast, blocking the GITR-GITR ligand (GITRL) interaction by GITR-Fc fusion protein abrogated inflammation and suppressed apoptosis of iNSPCs. Moreover, GITR-stimulated T cells caused apoptosis of the iNSPCs, and administration of GITR-stimulated T cells to poststroke severe combined immunodeficient mice significantly reduced iNSPC number compared with that of non-stimulated T cells. These observations indicate that among the CD4(+)T cells, GITR(+)CD4(+)T cells are major deteriorating modulators of poststroke neurogenesis. This suggests that blockade of the GITR-GITRL interaction may be a novel immune-based therapy in stroke.
authors: Laboratory of Neurogenesis and CNS Repair, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo 663-8501, Japan.
authors: M
authors: M
authors: Takata
authors: T
authors: T
authors: Nakagomi
authors: S
authors: S
authors: Kashiwamura
authors: A
authors: A
authors: Nakano-Doi
authors: O
authors: O
authors: Saino
authors: N
authors: N
authors: Nakagomi
authors: H
authors: H
authors: Okamura
authors: O
authors: O
authors: Mimura
authors: A
authors: A
authors: Taguchi
authors: T
authors: T
authors: Matsuyama
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology*; D016133:Polymerase Chain Reaction; D020521:Stroke / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein