T cell regeneration: an update on progress and challenges

T cells play essential roles in antitumor therapy.Via gene engineering technique to enhance tumor-antigen specificity,patient peripheral blood-derived T cells(PBT)show encouraging clinical outcomes in treating certain blood malignancies.However,the high costs,functionality exhaustion,and disease-condition-dependent availability of PBT prompt the attempts of exploring alternative T cell sources.Theoretically,induced T cells from pluripotent stem cells(PSC)are ideal candidates that integrate plenty of advantages that primary T cells lack,including unlimited off-the-shelf cell source and precision gene editing feasibility.However,researchers are still struggling with developing a straightforward protocol to induce functional and immunocompetent human T cells from PSC.Based on stromal cell-expressing or biomaterial-presenting Notch ligands DLL1 or DLL4,natural and induced blood progenitors can differentiate further toward T lineage commitment.However,none of the reported T induction protocols has yet translated into any clinical application,signaling the existence of numerous technical barriers for regenerating T cells functionally matching their natural PBT counterparts.Alternatively,new approaches have been developed to repopulate induced T lymphopoiesis via in vivo reprogramming or transplanting induced T cell precursors.Here,we review the most recent progress in the T cell regeneration field,and the remaining challenges dragging their clinical applications.