Mitochondrial respiration fuels adaptive immune responses: from immune synapse formation to T cell differentiation

Resumen

Defense against pathogenic microorganisms requires extensive communication between cells of the innate and adaptive immune system. T cell recognition of an antigen in the surface of an antigen-presenting cell (APC) leads to the formation of a specialized membrane-based structure at the interface of the APC and the T lymphocyte that favor transient cell-cell communication. This molecular assembly, termed immune synapse (IS) is a highly dynamic structure where polarized macromolecular components such as T cell receptors, adhesion molecules, cytoskeletal components and related organelles, orchestrate the early events of T cell activation. Following IS formation and T cell activation, T cells undergo a process of rapid clonal expansion and differentiation that give rise to the different types of effector and memory T cells. Immune signals and key metabolic cues present in the inflammatory milieu drive the expression of ‘lineage-specific’ transcription factors that ultimately guide the development of the different effector T cell subsets, which produce a specific repertoire of cytokines that determine the nature of the immune response and avoid autoimmune diseases. In this work, we have addressed the role of mitochondria in the regulation of adaptive immune responses. Our results uncover a fundamental role of mitochondria in almost every step of T cell function, starting with the control of IS organization and early TCR signaling to T cell differentiation, cytokine production and regulation of the outcome of immune responses. By regulating IS organization and the balance between OXPHOS and glycolysis, mitochondria provide a metabolic context appropriate for efficient regulation of inflammatory responses. In addition, we demonstrate a functional crosstalk of mitochondria and the biogenesis and function of endolysosomal compartment, linking for the first time mitochondrial deficiencies with lysosomal storage disorders.