Coshic, P. | bioRxiv Science

bioRxiv2026

A Glycolysis-Fatty Acid Metabolic Axis Shapes Human Tfh Cell Function

Follicular helper T (Tfh) cells orchestrate germinal centre-derived humoral immunity by providing essential help to B cells. Despite their key role in humoral immunity, the metabolic processes that guide Tfh differentiation and functions in human remain poorly understood. In this study, we used a human ex vivo Tfh differentiation model to investigate how key metabolic pathways influence Tfh cell differentiation and helper function. Human naive CD4 T cells were differentiated into Tfh cells, and glycolysis was selectively inhibited during early differentiation to assess its effects on cell fate, function, and transcriptomic landscape. Unexpectedly, early glycolytic inhibition enhanced Tfh cell differentiation but significantly impaired their function, including reduced IL-21 secretion and diminished B cell help. Transcriptomic analyses further revealed downregulation of fatty acid metabolic pathways when glycolysis was inhibited. To better understand this link, we disrupted fatty acid synthesis and oxidation and observed a marked decline in helper functions, including IL-21 and IFN-{gamma} production. Interestingly, acetate supplementation partially restored IFN-{gamma} secretion in glycolysis inhibited conditions, but not IL-21, suggesting that some functional requirements cannot be compensated by alternative metabolic sources. These findings identify glycolysis during early differentiation as a key regulator of human Tfh cells fate and reveal a glycolysis-dependent fatty acid metabolic axis that selectively controls Tfh function. This metabolic checkpoint provides mechanistic insight into tuning Tfh cells and Tfh-driven humoral immunity in vaccination and autoimmunity.

immunology↗

bioRxiv2018

Cell-intrinsic genetic regulation of peripheral memory-phenotype T cell frequencies

Memory T and B lymphocyte numbers are thought to be regulated by recent and cumulative microbial exposures. We report here that memory-phenotype lymphocyte frequencies in B, CD4 and CD8 T-cells in 3-monthly serial bleeds from healthy young adult humans were relatively stable over a 1-year period, while recently activated -B and -CD4 T cell frequencies were not, suggesting that recent environmental exposures affected steady state levels of recently activated but not of memory lymphocyte subsets. Frequencies of memory B and CD4 T cells were not correlated, suggesting that variation in them was unlikely to be determined by cumulative antigenic exposures. Immunophenotyping of adult siblings showed high concordance in memory, but not of recently activated lymphocyte subsets, suggesting genetic regulation of memory lymphocyte frequencies. To explore this possibility further, we screened effector memory (EM)-phenotype T cell frequencies in common independent inbred mice strains. Using two pairs from these strains that differed predominantly in either CD4EM and/or CD8EM frequencies, we constructed bi-parental bone marrow chimeras in F1 recipient mice, and found that memory T cell frequencies in recipient mice were determined by donor genotypes. Together, these data suggest cell-autonomous determination of memory T niche size, and suggest mechanisms maintaining immune variability.

immunology↗