Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo.
Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo.
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DOI：
10.4049/jimmunol.181.5.3137
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发表时间：
2008-09-01
期刊：
影响因子：
--
通讯作者：
Pease LR
中科院分区：
文献类型：
--
作者：
Radhakrishnan S;Cabrera R;Schenk EL;Nava-Parada P;Bell MP;Van Keulen VP;Marler RJ;Felts SJ;Pease LR
这是作者制作的手稿版本，已被《免疫学杂志》（The JI）接受出版。美国免疫学家协会(AAI)本书版权归《国际法》出版社所有。这一版本的手稿尚未由联合执行进行复制编辑或编辑校对;因此，它可能与联合执行发表的最后版本（在线和印刷版）不同。AAI（JI）对作者制作的手稿版本或美国国立卫生研究院或任何其他第三方从中衍生的任何版本中的错误或遗漏不承担责任。www.jimmunol.org淋巴细胞从幼稚的CD 4 + T细胞分化为成熟的Th 1、Th 2、Th 17或调节性T细胞（Treg）表型被认为是特征的终末阶段。在这里，我们证明了一种新的免疫调节剂B7-DC XAb（DCXAb）激活的DC可以重编程T细胞转化为T效应细胞。在体外或体内Treg：DCXAb相互作用后FoxP 3表达的下调是抗原特异性的、IL-6依赖性的，并且导致成熟T细胞表型的功能性重编程。重编程的TcB停止表达IL-10和TGFβ，不能抑制T细胞应答，并获得产生IFNγ、IL-17和TNFα的能力。IL-6+ DCXAb的能力和IL-6-/- DCXAb疫苗不能保护动物免于致命的黑色素瘤，这表明外源性调节的DC可以重编程宿主TCLs。为了支持这一假设并作为抗原特异性的测试，将DCXAb转移到RIP-OVA小鼠中会导致免疫耐受的破坏，从而诱导糖尿病。相反，将重编程的TcR细胞而不是类似处理的CD 25- T细胞过继转移到幼稚的RIP-OVA小鼠中也足以引起自身免疫性糖尿病。然而，用B7-DC XAb治疗正常小鼠未能引起全身性自身免疫。成熟的TcR可以被重编程为感受态效应细胞的发现为T细胞谱系的可塑性提供了新的见解，强调了DC：T细胞相互作用在平衡免疫与耐受性中的重要性，指出TcR是自身免疫效应物的储存库，并定义了一种新的方法，用于打破对自身抗原的耐受性作为癌症免疫治疗的策略。
This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), the publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org Lymphocyte differentiation from naïve CD4+ T cells into mature Th1, Th2, Th17, or T regulatory cell (Treg) phenotypes has been considered end stage in character. Here we demonstrate that DC activated with a novel immune modulator B7-DC XAb (DCXAb) can reprogram Tregs into T effector cells. Downregulation of FoxP3 expression after either in vitro or in vivo Treg:DCXAb interaction is antigen specific, IL-6-dependent, and results in the functional reprogramming of the mature T cell phenotype. The reprogrammed Tregs cease to express IL-10 and TGFβ, fail to suppress T cell responses, and gain the ability to produce IFNγ, IL-17, and TNFα. The ability of IL-6+ DCXAb and the inability of IL-6-/- DCXAb vaccines to protect animals from lethal melanoma suggest that exogenously modulated DC can reprogram host Tregs. In support of this hypothesis and as a test for antigen specificity, transfer of DCXAb into RIP-OVA mice causes a break in immune tolerance, inducing diabetes. Conversely, adoptive transfer of reprogrammed Tregs but not similarly treated CD25- T cells into naïve RIP-OVA mice is also sufficient to cause autoimmune diabetes. Yet, treatment of normal mice with B7-DC XAb fails to elicit generalized autoimmunity. The finding that mature Tregs can be reprogrammed into competent effector cells provides new insights into the plasticity of T cell lineage, underscores the importance of DC:T cell interactions in balancing immunity with tolerance, points to Tregs as a reservoir of autoimmune effectors, and defines a new approach for breaking tolerance to self antigens as a strategy for cancer immunotherapy.
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