Mucosal-associated invariant T (MAIT) cells participate in both protective immunity and pathogenesis of diseases. Most murine MAIT cells express an invariant TCRVα19-Jα33 (iVα19) TCR, which triggers signals crucial for their development. However, signal pathways downstream of the iVα19TCR and their regulation in MAIT cells are unknown. Diacylglycerol (DAG) is a critical second messenger that relays the TCR signal to multiple downstream signaling cascades. DAG is terminated by DAG kinase (DGK)-mediated phosphorylation and conversion to phosphatidic acid. We have demonstrated here that downregulation of DAG caused by enhanced DGK activity impairs late-stage MAIT cell maturation in both thymus and spleen. Moreover, deficiency of DGKζ but not DGKα by itself causes modest decreases in MAIT cells, and deficiency of both DGKα and ζ results in severe reductions of MAIT cells in an autonomous manner. Our studies have revealed that DAG signaling is not only critical but also must be tightly regulated by DGKs for MAIT cell development and that both DGKα and, more prominently, DGKζ contribute to the overall DGK activity for MAIT cell development.

中文翻译：

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分级的二酰基甘油激酶α和ζ活性可确保小鼠中与粘膜相关的不变T细胞发育。

粘膜相关不变T（MAIT）细胞参与保护性免疫和疾病的发病机制。大多数鼠类MAIT细胞表达不变的TCRVα19-Jα33（iVα19）TCR，该信号触发对其发育至关重要的信号。但是，iVα19TCR下游的信号通路及其在MAIT细胞中的调控尚不清楚。二酰基甘油（DAG）是将TCR信号中继到多个下游信号级联的关键第二信使。DAG通过DAG激酶（DGK）介导的磷酸化作用终止，并转化为磷脂酸。我们在这里证明了由增强的DGK活性引起的DAG的下调会损害胸腺和脾脏中晚期MAIT细胞的成熟。此外，缺乏DGKζ而不是缺乏DGKα本身会导致MAIT细胞适度减少，DGKα和ζ的缺乏会导致MAIT细胞以自主方式严重减少。我们的研究表明，DAG信号传导不仅对于MAIT细胞发育至关重要，而且必须受到DGK的严格调控，而且DGKα以及更重要的是DGKζ都对MAIT细胞发育的整体DGK活性做出了贡献。