TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function.
TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function.
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DOI：
10.1371/journal.pbio.1001674
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发表时间：
2013-10
期刊：
影响因子：
9.8
通讯作者：
Buch T
中科院分区：
文献类型：
--
作者：
Sledzińska A;Hemmers S;Mair F;Gorka O;Ruland J;Fairbairn L;Nissler A;Müller W;Waisman A;Becher B;Buch T
细胞因子 TGF-β 的信号传导可调节成熟的 CD4+ T 细胞群，但不参与调节性 T 细胞的存活和功能。人们普遍认为 TGF-β 对于调节性 T (Treg) 细胞的维持和功能以及外周耐受至关重要。小鼠胸腺发育过程中 TGF-β 受体 (TR) 的组成性消融突出了这一点，导致致命的自身免疫综合征。在这里，我们描述了 TGF-β 驱动的外周耐受不受成熟 CD4+ T 细胞上 TGF-β 信号传导的调节。特异性针对 CD4+ T 细胞的诱导型 TR2 消融不会导致致命的自身炎症。将这些 TR2 缺陷型 CD4+ T 细胞转移到淋巴细胞减少的受体中会导致结肠炎，但不会导致明显的自身免疫。相比之下，TR2 的胸腺消融与淋巴细胞减少相结合会导致致命的多器官炎症。有趣的是，成熟 CD4+ T 细胞上 TR2 的缺失不会导致 Treg 细胞群的崩溃，正如在本构模型中观察到的那样。相反，观察到调节性 T 细胞池和效应记忆 T 细胞池的显着扩大。这种扩张是细胞固有的，似乎是由 T 细胞受体敏感性增加引起的，与常见的伽马链依赖性细胞因子信号无关。 Foxp3和其他调节性T细胞标记物的表达不依赖于TGF-β信号传导，并且TR2缺陷的Treg细胞在体外和体内均保留了其抑制功能。总之，成熟 CD4+ T 细胞上 TGF-β 信号传导的缺失并不是造成外周耐受性破坏的原因，而是控制成年小鼠成熟 T 细胞的稳态。 TGF-β 是一种细胞因子，被认为对于免疫系统耐受性的维持和功能至关重要。在许多研究中，CD4+ T 细胞（一种协调免疫反应的白细胞）中 TGF-β 信号传导的破坏导致了自身免疫综合征。我们在此表明，从这些特殊的血细胞中诱导去除这种细胞因子受体会产生令人惊讶的温和结果。与预期相反，调节性T细胞的数量实际上增加了，而且我们发现这些细胞并不依赖于TGF-β信号传导。我们还表明，从成熟 CD4+ T 细胞中去除受体不会导致致命的自身炎症；只有当我们在细胞发育过程中去除受体时，我们才能看到先前在 TGF-β 受体消融的本构模型中报道的特征性致命多器官炎症。总之，我们的研究结果表明，尽管 TGF-β 调节成熟 CD4+ T 细胞的维持，但其信号对于该细胞群内的免疫耐受来说是可有可无的。
Signalling by the cytokine TGF-β regulates mature CD4+ T cell populations but is not involved in the survival and function of regulatory T cells. TGF-β is widely held to be critical for the maintenance and function of regulatory T (Treg) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-β receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-β–driven peripheral tolerance is not regulated by TGF-β signalling on mature CD4+ T cells. Inducible TR2 ablation specifically on CD4+ T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4+ T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4+ T cells does not result in the collapse of the Treg cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-β signalling and the TR2–deficient Treg cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-β signalling on mature CD4+ T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice. TGF-β is a cytokine thought to be critical for the maintenance and function of tolerance in the immune system. In many studies the disruption of TGF-β signalling in CD4+ T cells (a type of white blood cell that coordinates immune responses) has resulted in autoimmune syndromes. We show here that the induced removal of this cytokine's receptor from these specialised blood cells results in an astonishingly mild outcome. Contrary to expectations, the number of regulatory T cells is actually increased, and we find that these cells are not dependent on TGF-β signalling. We also show that removal of the receptor from mature CD4+ T cells does not lead to lethal autoinflammation; only when we removed the receptor during development of the cells did we see the characteristic lethal multi-organ inflammation reported previously in constitutive models of TGF-β receptor ablation. In summary, our findings indicate that although TGF-β regulates maintenance of mature CD4+ T cells, its signals are dispensable for immune tolerance within this cell population.
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20.3
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