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

Foreign and self-antigens activate CD4 conventional and regulatory T cells (Tregs) to promote immunity and tolerance, respectively. These cell populations, which depend on interleukin-2 (IL-2), are being expanded and engineered for adoptive cell therapy (ACT) for cancer and autoimmunity. Here, we investigate the molecular pathways underlying the 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, T effector (Teff) cells showed greater expansion that was 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 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 .