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- Title
Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke.
- Authors
Takata, M; Nakagomi, T; Kashiwamura, S; Nakano-Doi, A; Saino, O; Nakagomi, N; Okamura, H; Mimura, O; Taguchi, A; Matsuyama, T
- 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.
- Publication
Cell death and differentiation, 2012, Vol 19, Issue 5, p756
- ISSN
1476-5403
- Publication type
Journal Article
- DOI
10.1038/cdd.2011.145