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

Abstract

                T-cell receptor (TCR)-induced Ca
                2+
                signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca
                2+
                to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca
                2+
                -uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca
                2+
                (
                m
                Ca
                2+
                ) uptake in primary naive and effector human CD4
                +
                T-cells. Compared to naive T-cells, effector T-cells display elevated
                m
                Ca
                2+
                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
                m
                Ca
                2+
                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
                m
                Ca
                2+
                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.