Growth control of human regulatory CD4+ T cells is more tightly controlled than T effector cells due to distinctive molecular programming

Here, we investigate the molecular pathways underlying the in vitro expansion of human CD4+ Teff and Tregs to TCR/CD28/IL-2 signaling over 12 days. Temporal integration of differential chromatin accessibility and gene expression revealed similar responses over the first 6 days. After this time, Teff cells showed greater expansion associated with more robust gene activation and chromatin opening that supported increased activation of mTORC1-dependent signaling and a more energetic phenotype. Thus, Tregs are programmed temporally for more limited expansion in vitro that may benefit ACT for cancer but may be a drawback for autoimmunity. These findings may reflect a mechanism to finely tune Treg numbers to maintain homeostasis in vivo.