Mitochondrial Complex II Orchestrates Divergent Effects in CD4+ and CD8+ T Cells

Mitochondrial metabolism orchestrates T-cell functions, yet the role of specific mitochondrial components in distinct T-cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T-cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A (SDHA), deficient mice, we integrated single-cell RNA sequencing and metabolic profiling, with in vitro and in vivo T-cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T-cells. In CD4+ T-cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell-mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T-cells reduced OXPHOS, but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA KO CD8+ T-cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T-cells.