STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model.
STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model.
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DOI：
10.4049/jimmunol.0903006
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Luznik L
中科院分区：
文献类型：
--
作者：
Radojcic V;Pletneva MA;Yen HR;Ivcevic S;Panoskaltsis-Mortari A;Gilliam AC;Drake CG;Blazar BR;Luznik L
供体CD4+ T细胞被认为是诱导慢性移植物抗宿主病（GVHD）中迟发性宿主组织损伤所必需的。然而，不同的效应CD4+ T细胞亚群的相对贡献和影响其产生的分子途径尚不清楚。我们研究了STAT3通路在慢性硬皮病GVHD小鼠模型中的作用。该途径整合了幼稚CD4+ T细胞分化过程中的多种信号传导事件，并影响其稳态。我们报告说，嵌合体接受含有STAT3消融供体CD4+ T细胞的同种异体移植物不会产生同种免疫组织损伤的经典临床和病理表现。嵌合体的分析显示，STAT3信号传导的消除减少了供体来源的CD4+ T细胞的体内扩增及其在GVHD靶组织中的积累，而没有消除抗宿主同种异体反应性。STAT3消融并不显著影响Th1分化，同时通过胸腺依赖性和非依赖性途径增强CD4+CD25+Foxp3+ T细胞重建。接受STAT3缺陷型T细胞的嵌合体中CD25+ T细胞的瞬时消耗导致同种免疫肠道和肝脏损伤的延迟发展。这种迟发性从头GVHD与供体造血干细胞（HSC）来源的Th1和Th17细胞的出现有关。这些结果表明，移植物CD4+ T细胞中的STAT3信号传导将供体移植物T细胞的同种免疫组织损伤和供体HSC衍生的致病性效应细胞的出现联系起来，并且这两个群体都有助于在小鼠模型中同种异体骨髓移植后慢性GVHD的发生，尽管方式不同。
Donor CD4+ T-cells are thought to be essential for inducing delayed host tissue injury in chronic graft-versus-host disease (GVHD). However, the relative contributions of distinct effector CD4+ T-cell subpopulations and the molecular pathways influencing their generation are not known. We investigated the role of the STAT3 pathway in a murine model of chronic sclerodermatous GVHD. This pathway integrates multiple signaling events during the differentiation of naïve CD4+ T-cells and impacts their homeostasis. We report that chimeras receiving an allograft containing STAT3-ablated donor CD4+ T-cells do not develop classical clinical and pathological manifestations of alloimmune tissue injury. Analysis of chimeras showed that abrogation of STAT3 signaling reduced in vivo expansion of donor-derived CD4+ T-cells and their accumulation in GVHD target tissues without abolishing anti-host alloreactivity. STAT3 ablation did not significantly affect Th1 differentiation while enhancing CD4+CD25+Foxp3+ T-cell reconstitution through both thymus-dependent and -independent pathways. Transient depletion of CD25+ T-cells in chimeras receiving STAT3-deficient T-cells resulted in delayed development of alloimmune gut and liver injury. This delayed de novo GVHD was associated with the emergence of donor hematopoietic stem cell (HSC)-derived Th1 and Th17 cells. These results suggest that STAT3 signaling in graft CD4+ T-cells links the alloimmune tissue injury of donor graft T-cells and the emergence of donor HSC-derived pathogenic effector cells and that both populations contribute, albeit in different ways, to the genesis of chronic GVHD after allogeneic bone marrow transplantation in a murine model.
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