D-Lactate drives cytotoxicity in Th1 cells by limiting mitochondrial ROS production through enhanced glyoxalase system activity

Abstract

CD4+ T lymphocytes with cytotoxic activity are an understudied T helper (Th) cell population with the capacity to orchestrate immune responses and kill target cells in a TCR-restricted manner. Particularly, the mechanisms that promote the differentiation of cytotoxic Th cells remain elusive. Here, by supplementing Th1 cells with different lactate stereoisomers, we identify a previously unrecognized stereospecific adaptation that reinforces cytotoxic and proinflammatory programs. Although both D- and L-lactate impacted histone acetylation and metabolic activity, only D-lactate increased IFN-{gamma} and TNF- production and most potently promoted cytotoxic function. D-lactate also selectively enhanced mTORC1 and ERK1/ERK2 signaling, although these changes were not sufficient to fully explain the distinctive phenotype. Instead, the decisive feature of D-lactate supplementation was a reduction in mitochondrial reactive oxygen species (ROS), associated with electron transport chain (ETC) remodeling and enhanced glyoxalase-dependent buffering. Together, these findings identify a stereospecific lactate redox axis promoting cytotoxic Th1 cell differentiation.