Glycolysis‐Dependent Fatty Acid Metabolism Supports Human Tfh Cell Function

Follicular helper T (Tfh) cells orchestrate germinal center (GC) derived humoral immunity by providing essential help to B cells. Despite their key role in humoral immunity, the metabolic cues that shape Tfh cell differentiation and functions in humans remain poorly understood. Here, using a human ex vivo Tfh cell differentiation model, we investigated the metabolic requirements of Tfh cell development and function through targeted metabolic perturbation of glycolysis and fatty acid metabolism, transcriptomic analyses, and metabolic rescue experiments. Unexpectedly, early glycolytic inhibition enhanced Tfh cell differentiation but markedly impaired function, including reduced IL-21 production and diminished B-cell help. Transcriptomic and metabolic analyses revealed that glycolytic inhibition was accompanied by suppression of fatty acid metabolism. Consistently, independent inhibition of fatty acid synthesis or oxidation suppressed Tfh cell help functions, including IL-21 and IFN-γ production, as well as B-cell help potential. Interestingly, acetate supplementation partially restored IFN-γ secretion in glycolysis-inhibited conditions, but not IL-21, indicating limited metabolic compensation. Together, these findings reveal distinct metabolic requirements for Tfh cell differentiation and function and identify glycolysis-dependent fatty acid metabolism as an important determinant of human Tfh cell functional competence. This metabolic crosstalk provides new insight into the regulation of Tfh cells and Tfh-driven humoral immunity in vaccination and autoimmunity.