Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis
Astrocytic Fas ligand expression is required to induce T‐cell apoptosis and recovery from experimental autoimmune encephalomyelitis
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DOI：
10.1002/eji.201242679
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发表时间：
2013-01
影响因子：
5.4
通讯作者：
Xu Wang;Fahad Haroon;S. Karray;Martina Deckert;D. Schlüter
中科院分区：
文献类型：
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作者：
Xu Wang;Fahad Haroon;S. Karray;Martina Deckert;D. Schlüter
在T细胞介导的中枢神经系统自身免疫性疾病中，FasL诱导Fas+ T细胞凋亡有助于疾病的解决。然而，诱导细胞凋亡的细胞群仍有待确定。为了研究星形胶质细胞FasL在实验性自身免疫性脑脊髓炎中调控T细胞凋亡中的作用，我们用MOG35-55肽选择性免疫星形胶质细胞中缺乏FasL的C57BL/6胶质纤维酸蛋白(GFAP) - Cre FasLfl/fl小鼠。GFAP‐Cre FasLfl/fl小鼠无法解决EAE，并遭受持续脱髓鞘和瘫痪，而FasLfl/fl对照组小鼠恢复。与FasLfl/fl小鼠相比，GFAP‐Cre FasLfl/fl小鼠在免疫后15天（对照小鼠最大临床疾病时间点）后未能诱导Fas+激活的CD4+ T细胞凋亡和Foxp3+ Treg细胞数量增加。在GFAP - Cre FasLfl/fl小鼠中，持续激活和产生GM - CSF的CD4+ T细胞也导致CNS中IL - 17、IFN - γ、TNF和GM - CSF mRNA表达增加。在体外，FasL+而非FasL−星形胶质细胞诱导caspase‐3的表达和活化T细胞的凋亡。综上所述，星形胶质细胞FasL的表达在控制和消除CNS自身免疫T细胞中起重要作用，从而决定EAE的恢复情况。
In T‐cell‐mediated autoimmune diseases of the CNS, apoptosis of Fas+ T cells by FasL contributes to resolution of disease. However, the apoptosis‐inducing cell population still remains to be identified. To address the role of astrocytic FasL in the regulation of T‐cell apoptosis in experimental autoimmune encephalomyelitis, we immunized C57BL/6 glial fibrillary acid protein (GFAP)‐Cre FasLfl/fl mice selectively lacking FasL in astrocytes with MOG35–55 peptide. GFAP‐Cre FasLfl/fl mice were unable to resolve EAE and suffered from persisting demyelination and paralysis, while FasLfl/fl control mice recovered. In contrast to FasLfl/fl mice, GFAP‐Cre FasLfl/fl mice failed to induce apoptosis of Fas+ activated CD4+ T cells and to increase numbers of Foxp3+ Treg cells beyond day 15 post immunization, the time point of maximal clinical disease in control mice. The persistence of activated and GM‐CSF‐producing CD4+ T cells in GFAP‐Cre FasLfl/fl mice also resulted in an increased IL‐17, IFN‐γ, TNF, and GM‐CSF mRNA expression in the CNS. In vitro, FasL+ but not FasL− astrocytes induced caspase‐3 expression and apoptosis of activated T cells. In conclusion, FasL expression of astrocytes plays an important role in the control and elimination of autoimmune T cells from the CNS, thereby determining recovery from EAE.