期刊
CELL DEATH AND DIFFERENTIATION
卷 19, 期 5, 页码 756-767出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2011.145
关键词
GITR; Fas; T-cell; neural stem cell; ischemia
资金
- Ministry of Education, Culture, Sports, Science and Technology [21590473]
- Hyogo Science and Technology Association
- Grants-in-Aid for Scientific Research [21590473, 24591740, 21500359] Funding Source: KAKEN
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. Cell Death and Differentiation (2012) 19, 756-767; doi:10.1038/cdd.2011.145; published online 4 November 2011
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