Malt1 self-cleavage is critical for regulatory T cell homeostasis and anti-tumor immunity in mice.
Malt1 self-cleavage is critical for regulatory T cell homeostasis and anti-tumor immunity in mice.
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MALT1自切解对于小鼠的调节T细胞稳态和抗肿瘤免疫至关重要。
DOI：
10.1002/eji.201847597
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发表时间：
2018-10
影响因子：
5.4
通讯作者：
Bornschein S
中科院分区：
文献类型：
--
作者：
Baens M;Stirparo R;Lampi Y;Verbeke D;Vandepoel R;Cools J;Marynen P;de Bock CE;Bornschein S
粘膜相关淋巴组织1（Malt 1）通过其衔接子和蛋白水解功能介导核因子κB（NF-κB）信号传导的激活来调节免疫细胞功能。Malt 1也是其自身蛋白酶活性的靶点，这种自我切割进一步促进NF-κB活性。到目前为止，Malt 1自切割和其一般蛋白酶功能在调节NF-κB信号传导和免疫激活中的功能差异仍不清楚。在这里，我们使用一种新的小鼠模型证明了Malt 1自我切割在调节NF-κB靶基因表达和随后的T细胞活化中的重要性。值得注意的是，我们进一步确定Treg稳态通过Treg内在和外在机制与Malt 1功能密切相关。发现TCR介导的Malt 1蛋白水解活性和自切割驱动常规CD 4 + T细胞中的IL 2表达，从而调节IL 2对Treg稳态的可用性。值得注意的是，单独的Malt 1介导的自切割的丧失足以引起显著的Treg缺陷，导致抗肿瘤免疫反应性增加，而没有相关的自身免疫并发症。这些结果首次证实，抑制MALT 1蛋白水解活性可能是增强抗肿瘤免疫力的可行治疗策略。
Mucosa‐associated lymphoid tissue 1 (Malt1) regulates immune cell function by mediating the activation of nuclear factor κB (NF‐κB) signaling through both its adaptor and proteolytic function. Malt1 is also a target of its own protease activity and this self‐cleavage further contributes to NF‐κB activity. Until now, the functional distinction between Malt1 self‐cleavage and its general protease function in regulating NF‐κB signaling and immune activation remained unclear. Here we demonstrate, using a new mouse model, the importance of Malt1 self‐cleavage in regulating expression of NF‐κB target genes and subsequent T cell activation. Significantly, we further establish that Treg homeostasis is critically linked to Malt1 function via a Treg intrinsic and extrinsic mechanism. TCR‐mediated Malt1 proteolytic activity and self‐cleavage was found to drive Il2 expression in conventional CD4+ T cells, thereby regulating Il2 availability for Treg homeostasis. Remarkably, the loss of Malt1‐mediated self‐cleavage alone was sufficient to cause a significant Treg deficit resulting in increased anti‐tumor immune reactivity without associated autoimmunity complications. These results establish for the first time that inhibition of MALT1 proteolytic activity could be a viable therapeutic strategy to augment anti‐tumor immunity.
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影响因子：
8.8
作者：
Gewies, Andreas;Gorka, Oliver;Ruland, Juergen
通讯作者：
Ruland, Juergen
影响因子：
30.5
作者：
Coornaert, Beatrice;Baens, Mathijs;Beyaert, Rudi
通讯作者：
Beyaert, Rudi
影响因子：
14.2
作者：
Humblet-Baron, Stephanie;Franckaert, Dean;Liston, Adrian
通讯作者：
Liston, Adrian
影响因子：
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作者：
Luu M;Jenike E;Vachharajani N;Visekruna A
通讯作者：
Visekruna A
影响因子：
56.9
作者：
Ruefli-Brasse, AA;French, DM;Dixit, VM
通讯作者：
Dixit, VM