Mitochondrial calcium uniporter complex controls T‑cell‑mediated immune responses

Sustained and balanced calcium (Ca2+) increase upon T-cell receptor activation is a fundamental process that regulates essential T-cell functions including proliferation, clonal expansion and cytokine secretion. In this context, mitochondria play an important role and take up Ca2+ to support the elevated bioenergetic demands. Accordingly, alterations in the protein machinery that regulates mitochondrial Ca2+ (mCa2+) flux across the inner mitochondrial membrane; the mitochondrial calcium uniporter (MCU) complex, could be implicated in T-cell immunity. However, the exact role of mCa2+, and thus MCU in T-cells is not fully understood. Here, we show that upon activation of primary human CD4+ T-cells, the MCU complex undergoes a time-dependent compositional rearrangement that causes elevated mCa2+ uptake and increased mitochondrial bioenergetic output. Transcriptome and proteome analyses of naive and effector CD4+ T-cells reveal molecular determinants involved in mitochondrial and T-cell functional reprograming. Moreover, they identify genes, proteins and signaling pathways controlled by mitochondrial Ca2+ homeostasis i.e. the MCU. MCUa knockdown (KD) diminishes mCa2+, mitochondrial respiration and ATP production as well as T-cell invasion and cytokine secretion. In vivo, downregulation of MCUa in rat CD4+ T-cells suppresses autoimmune responses in a multiple sclerosis model of inflammatory experimental autoimmune encephalomyelitis (EAE). In summary, our findings imply that mCa2+ uptake through MCU is essential for proper T-cell function and is involved in autoimmunity. Specific MCU inhibitors targeting T-cells could be beneficial for autoimmune suppression and control of immune system dysregulation.

T细胞受体（T-cell receptor）激活后出现的持续且稳态的钙离子（Ca²+）升高，是调控T细胞核心功能的基础过程，这些核心功能包括细胞增殖、克隆扩增与细胞因子分泌。在此过程中，线粒体发挥关键作用，通过摄取Ca²+以满足细胞升高的生物能量需求。据此，调控线粒体内膜两侧线粒体钙离子（mitochondrial Ca²+, mCa²+）流动的蛋白质机器——线粒体钙离子单向转运体（mitochondrial calcium uniporter, MCU）复合物的异常，可能与T细胞免疫功能相关。然而，目前尚未完全明确mCa²+以及MCU在T细胞中的具体作用。
本研究发现，原代人CD4+ T细胞激活后，MCU复合物会发生时间依赖性的组成重排，进而提升mCa²+摄取效率并增强线粒体生物能量输出。对初始T细胞（naive T cell）与效应性CD4+ T细胞进行转录组（transcriptome）与蛋白质组（proteome）分析，揭示了参与线粒体及T细胞功能重编程的分子决定因素。此外，该分析还鉴定出受线粒体Ca²+稳态（由MCU介导调控）的基因、蛋白质及信号通路。MCUa敲低（knockdown, KD）会削弱mCa²+摄取、线粒体呼吸与ATP生成能力，同时抑制T细胞侵袭及细胞因子分泌。
体内实验显示，大鼠CD4+ T细胞中MCUa的下调，会在炎症性实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）——多发性硬化的经典动物模型——中抑制自身免疫反应。综上，本研究结果表明，通过MCU介导的mCa²+摄取对于T细胞正常功能至关重要，且参与自身免疫过程。靶向T细胞的特异性MCU抑制剂或可用于自身免疫抑制及免疫系统失调的调控。