Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery.
Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery.
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DOI：
10.1371/journal.pbio.1000051
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发表时间：
2009-03-03
期刊：
影响因子：
9.8
通讯作者：
Hoebe K
中科院分区：
文献类型：
--
作者：
Barnes MJ;Krebs P;Harris N;Eidenschenk C;Gonzalez-Quintial R;Arnold CN;Crozat K;Sovath S;Moresco EM;Theofilopoulos AN;Beutler B;Hoebe K
在胸腺选择过程中，表达叉头盒P3(Foxp3)的调节性T(Treg)细胞出现在具有适度自反应性T细胞受体的胸腺细胞中。体外研究表明，Foxp3也可以通过细胞因子依赖的方式在外周CD4+T细胞中诱导。胸腺或外周来源的Treg细胞在体内可能具有不同的功能，但在野生型小鼠中，这两个群体的表型难以区分。在这里，我们显示了Carma1点突变的小鼠缺乏胸腺CD4+Foxp3+Treg细胞，并证明了在胸腺Foxp3诱导中对CARMA1的细胞内在需求。然而，在细胞因子转化生长因子β(β)和白介素2(IL-2)的作用下，外周血Carma1缺陷的Treg细胞可以在体外产生和扩增。在体内，存在一个小的外周Treg池，该池在粘膜部位丰富，并可在感染小鼠巨细胞病毒(MCMV)后全身扩张。我们的数据为控制调节性T细胞谱系承诺的两种不同机制提供了遗传学证据。此外，我们还表明，外周Treg细胞是一个动态的群体，可能会扩大以限制免疫病理或促进慢性感染。在哺乳动物中，CD4+T细胞对于控制感染是必不可少的，但也有可能攻击宿主组织，导致自身免疫性疾病。CD4+T细胞的一个亚群，调节性T细胞(Treg)--由叉头转录因子Foxp3的表达识别--通过抑制免疫反应来预防免疫病理。这些细胞在CD4+T细胞亚群中是独一无二的，因为只有Treg血统可以在胸腺和外周发育。使用遗传学方法，我们发现了Carma1基因的突变，Carma1是T和B细胞信号的关键组成部分，在小鼠中，它区分了来自外周的Treg细胞和来自胸腺的调节性T细胞。这种突变导致了胸腺Treg细胞的缺失。然而，在Carma1突变小鼠的脾、淋巴结和结肠中观察到少量Treg细胞，这些细胞在病毒感染后扩张，这表明Treg细胞仍然可以外周发育。事实上，Carma1突变的CD4+T细胞可以在体外转化为Treg血统。我们的结果表明，发育中的胸腺细胞需要CARMA1信号通路才能成为Treg细胞，但幼稚的CD4+T细胞可以在外围绕过。这种二分法表明，胸腺或外周来源的Treg细胞在体内可能具有不同的特异性或功能。胸腺对CARMA1依赖信号的器官特异性要求表明，胸腺或外周来源的调节性T细胞在体内可能具有不同的作用。
Regulatory T (Treg) cells expressing forkhead box P3 (Foxp3) arise during thymic selection among thymocytes with modestly self-reactive T cell receptors. In vitro studies suggest Foxp3 can also be induced among peripheral CD4+ T cells in a cytokine dependent manner. Treg cells of thymic or peripheral origin may serve different functions in vivo, but both populations are phenotypically indistinguishable in wild-type mice. Here we show that mice with a Carma1 point mutation lack thymic CD4+Foxp3+ Treg cells and demonstrate a cell-intrinsic requirement for CARMA1 in thymic Foxp3 induction. However, peripheral Carma1-deficient Treg cells could be generated and expanded in vitro in response to the cytokines transforming growth factor beta (TGFβ) and interleukin-2 (IL-2). In vivo, a small peripheral Treg pool existed that was enriched at mucosal sites and could expand systemically after infection with mouse cytomegalovirus (MCMV). Our data provide genetic evidence for two distinct mechanisms controlling regulatory T cell lineage commitment. Furthermore, we show that peripheral Treg cells are a dynamic population that may expand to limit immunopathology or promote chronic infection. In mammals, CD4+ T cells are essential for controlling infections, but have the potential to attack host tissues as well, resulting in autoimmune disease. A subset of CD4+ T cells, regulatory T cells (Treg)—identified by the expression of the forkhead transcription factor Foxp3—serve to prevent immunopathology by dampening immune responses. These cells are unique among CD4+ T cell subsets, as only the Treg lineage can develop in both the thymus and periphery. Using a genetic approach, we identified a mutation in the gene Carma1, a key component of T and B cell signaling, which in mice distinguishes Treg cells derived from the periphery from thymic-derived regulatory T cells. The mutation caused an absence of thymic Treg cells. However, a small population of Treg cells was observed in the spleen, lymph nodes, and colon of Carma1-mutant mice that expanded after viral infection, suggesting that peripheral development of Treg cells could still occur. Indeed, Carma1-mutant CD4+ T cells could be converted into the Treg lineage in vitro. Our results demonstrate an organ-specific requirement for the CARMA1 signaling pathway that developing thymocytes need in order to become Treg cells, but that naïve CD4+ T cells can bypass in the periphery. This dichotomy suggests that Treg cells of thymic or peripheral origin may have different specificities or functions in vivo. The organ-specific requirement for CARMA1-dependent signaling in the thymus suggests that regulatory T cells of thymic or peripheral origin may have different roles in vivo.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
4.4
作者：
Burchill, Matthew A.;Yang, Jianying;Farrar, Michael A.
通讯作者：
Farrar, Michael A.
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
DOI：
10.1038/nri2335
发表时间：
2008-06
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.151174198
发表时间：
2001-07-31
影响因子：
11.1
作者：
Iwashiro, M;Messer, RJ;Hasenkrug, KJ
通讯作者：
Hasenkrug, KJ