IL-10 produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-iTregs during immunotherapy.
IL-10 produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-iTregs during immunotherapy.
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DOI：
10.4049/jimmunol.1200936
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发表时间：
2012-12-15
期刊：
影响因子：
--
通讯作者：
Williams CB
中科院分区：
文献类型：
--
作者：
Schmitt EG;Haribhai D;Williams JB;Aggarwal P;Jia S;Charbonnier LM;Yan K;Lorier R;Turner A;Ziegelbauer J;Georgiev P;Simpson P;Salzman NH;Hessner MJ;Broeckel U;Chatila TA;Williams CB
表达转录因子Foxp 3并产生IL-10的“天然”调节性T（nTreg）细胞是全身免疫耐受所需的。“诱导的”Treg（iTreg）细胞是非冗余的，并且对于粘膜表面的耐受性是必需的，然而它们的抑制和稳定性机制是未知的。我们研究了iTreg细胞产生的IL-10和iTreg细胞命运在炎症性肠病治疗模型中的作用。通过过继转移携带无功能Foxp 3等位基因的幼稚CD 4 + T细胞，在Rag 1 −/−小鼠中诱导结肠炎。在体重减轻开始时，用iTreg和nTreg细胞治疗小鼠，其中一个标记的亚群选择性地缺乏IL-10。体重评估、组织学评分、细胞因子分析和流式细胞术用于监测疾病活动。使用转录谱分析和TCR库分析来追踪细胞命运。当存在nTreg细胞但IL-10缺乏时，iTreg细胞产生的IL-10对于疾病的治疗是必要且足够的，反之亦然。然而，约85%的转移的iTreg细胞失去Foxp 3表达（ex-iTreg），但保留了iTreg转录组的一部分，这未能限制它们在再转移时的致病潜力。TCR库分析显示，在小鼠内或用相同细胞处理的小鼠之间，iTreg和ex-iTreg细胞之间没有克隆关系。这些数据确定了维持粘膜耐受性的Treg亚群之间的动态IL-10依赖性功能相互作用。支持稳定iTreg细胞的生态位是有限的并且容易饱和，这在免疫治疗期间促进了具有致病潜力的大量ex-iTreg细胞。
“Natural” regulatory T (nTreg) cells that express the transcription factor Foxp3 and produce IL-10 are required for systemic immunological tolerance. “Induced” Treg (iTreg) cells are non-redundant and essential for tolerance at mucosal surfaces, yet their mechanisms of suppression and stability are unknown. We investigated the role of iTreg cell-produced IL-10 and iTreg cell fate in a treatment model of inflammatory bowel disease. Colitis was induced in Rag1−/− mice by the adoptive transfer of naïve CD4+ T cells carrying a non-functional Foxp3 allele. At the onset of weight loss, mice were treated with both iTreg and nTreg cells where one marked subset was selectively IL-10-deficient. Body weight assessment, histological scoring, cytokine analysis, and flow cytometry were used to monitor disease activity. Transcriptional profiling and TCR repertoire analysis were used to track cell fate. When nTreg cells were present but IL-10 deficient, iTreg cell-produced IL-10 was necessary and sufficient for the treatment of disease, and vice versa. Invariably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome, which failed to limit their pathogenic potential upon retransfer. TCR repertoire analysis revealed no clonal relationships between iTreg and ex-iTreg cells, either within mice or between mice treated with the same cells. These data identify a dynamic IL-10-dependent functional reciprocity between Treg subsets that maintains mucosal tolerance. The niche supporting stable iTreg cells is limited and readily saturated, which promotes a large population of ex-iTreg cells with pathogenic potential during immunotherapy.
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影响因子：
32.4
作者：
Hill, Jonathan A.;Feuerer, Markus;Benoist, Christophe
通讯作者：
Benoist, Christophe
影响因子：
15.3
作者：
Apostolou, I;von Boehmer, H
通讯作者：
von Boehmer, H
影响因子：
32.4
作者：
Haribhai D;Williams JB;Jia S;Nickerson D;Schmitt EG;Edwards B;Ziegelbauer J;Yassai M;Li SH;Relland LM;Wise PM;Chen A;Zheng YQ;Simpson PM;Gorski J;Salzman NH;Hessner MJ;Chatila TA;Williams CB
通讯作者：
Williams CB
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
4.4
作者：
DiPaolo, Richard J.;Brinster, Carine;Shevach, Ethan M.
通讯作者：
Shevach, Ethan M.