Abstract
Human induced pluripotent stem cells (iPSCs) provide a potentially unlimited resource for cell therapies, but the derivation of mature cell types remains challenging. The histone methyltransferase EZH1 is a negative regulator of lymphoid potential during embryonic hematopoiesis. Here, we demonstrate that EZH1 repression facilitates invitro differentiation and maturation of Tcells from iPSCs. Coupling a stroma-free Tcell differentiation system with EZH1-knockdown-mediated epigenetic reprogramming, we generated iPSC-derived Tcells, termed EZ-T cells, which display a highly diverse Tcell receptor (TCR) repertoire and mature molecular signatures similar to those of TCRαβ Tcells from peripheral blood. Upon activation, EZ-T cells give rise to effector and memory Tcell subsets. When transduced with chimeric antigen receptors (CARs), EZ-T cells exhibit potent antitumor activities invitro and in xenograft models. Epigenetic remodeling via EZH1 repression allows efficient production of developmentally mature Tcells from iPSCs for applications in adoptive cell therapy.
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