MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner
MALT1 Proteolytic Activity Suppresses Autoimmunity in a T Cell Intrinsic Manner
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DOI：
10.3389/fimmu.2019.01898
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发表时间：
2019-08-14
影响因子：
7.3
通讯作者：
Beyaert, Rudi
中科院分区：
文献类型：
--
作者：
Demeyer, Annelies;Skordos, Ioannis;Beyaert, Rudi
MALT 1通过调节NF-κ B和不同细胞类型中的其他关键信号传导途径，是先天性和适应性免疫中的中心信号传导组分。MALT 1的活性由其支架和蛋白酶功能介导。由于其在淋巴细胞活化和增殖中的作用，MALT 1蛋白水解活性的抑制对于自身免疫和某些淋巴瘤的治疗靶向具有高度意义。然而，最近的研究表明，Mak 1蛋白酶死亡敲入（Malt 1-PD）小鼠患有自身免疫性疾病，这在一定程度上缓和了最初的热情。尽管已经提出免疫抑制调节性T细胞（TCLs）和活化的效应CD 4（+）T细胞之间的不平衡在Malt 1-PD小鼠的自身免疫表型中起关键作用，但T细胞中MALT 1蛋白水解活性的具体贡献仍不清楚。使用T细胞条件性Malt 1蛋白酶死亡敲入（Malt 1-PDT）小鼠，我们在这里证明，MALT 1在调节胸腺和外周T细胞的稳态和功能中具有T细胞内在的作用。MALT 1蛋白水解活性的T细胞特异性消融表型复制小鼠，其中MALT 1蛋白水解活性在所有细胞类型中已被遗传失活。Malt 1-PDT小鼠胸腺和外周中的Treg数量减少，尽管与全身Malt 1-PD小鼠相比，外周中的效果不太明显，表明其他细胞类型也可能以MALT 1蛋白酶依赖性方式促进Treg诱导。尽管外周Treg数量存在差异，但T细胞特异性和全身Malt 1-PD小鼠均发生共济失调和多器官炎症，程度相似。此外，用野生型人MALT 1的T细胞特异性表达重建全身Malt 1-PD小鼠消除了自身免疫的所有迹象。总之，这些发现确立了MALT 1蛋白水解活性在抑制自身免疫反应中的重要T细胞内在作用。
MALT1 is a central signaling component in innate and adaptive immunity by regulating NF-kappa B and other key signaling pathways in different cell types. Activities of MALT1 are mediated by its scaffold and protease functions. Because of its role in lymphocyte activation and proliferation, inhibition of MALT1 proteolytic activity is of high interest for therapeutic targeting in autoimmunity and certain lymphomas. However, recent studies showing that Mak1 protease-dead knock-in (Malt1-PD) mice suffer from autoimmune disease have somewhat tempered the initial enthusiasm. Although it has been proposed that an imbalance between immune suppressive regulatory T cells (Tregs) and activated effector CD4(+) T cells plays a key role in the autoimmune phenotype of Malt1-PD mice, the specific contribution of MALT1 proteolytic activity in T cells remains unclear. Using T cell-conditional Malt1 protease-dead knock-in (Malt1-PDT) mice, we here demonstrate that MALT1 has a T cell-intrinsic role in regulating the homeostasis and function of thymic and peripheral T cells. T cell-specific ablation of MALT1 proteolytic activity phenocopies mice in which MALT1 proteolytic activity has been genetically inactivated in all cell types. The Malt1-PDT mice have a reduced number of Tregs in the thymus and periphery, although the effect in the periphery is less pronounced compared to full-body Malt1-PD mice, indicating that also other cell types may promote Treg induction in a MALT1 protease-dependent manner. Despite the difference in peripheral Treg number, both T cell-specific and full-body Malt1-PD mice develop ataxia and multi-organ inflammation to a similar extent. Furthermore, reconstitution of the full-body Malt1-PD mice with T cell-specific expression of wild-type human MALT1 eliminated all signs of autoimmunity. Together, these findings establish an important T cell-intrinsic role of MALT1 proteolytic activity in the suppression of autoimmune responses.