Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.

Abstract

T-cell receptor (TCR)-induced Ca²⁺ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca²⁺ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca²⁺-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca²⁺ (_mCa²⁺) uptake in primary naive and effector human CD4⁺ T-cells. Compared to naive T-cells, effector T-cells display elevated _mCa²⁺ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUa_KD), diminishes _mCa²⁺ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUa_KD in rat CD4⁺ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that _mCa²⁺ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.