Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity.CD4+ and CD8+ T cells are key players in cellular immunity with distinct functions.Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses.During thymic maturation,Thpok,HDAC1 and HDAC2 guard CD4+ T cells from activation of CD8+ cytotoxic genes,and Tcf1 and Lef1 utilize their intrinsic HDAC activity to shut down CD4+ lineage-associated genes in CD8+ T cells.In activated CD4+ T cells,Tcf1 and Lef1 act upstream of the Bcl6-Blimp1 axis to direct differentiation of follicular helper T (Tfh) cells,and prevent diversion of Tfh to IL-17-producing cells.In parallel,T-bet,together with Eomes or Bllmp1,ensures proper induction of the cytotoxic program in CD8+ effectors elicited by acute infection,and prevents generation of pathogenic,IL-17-producing CD8+ effector T cells.Antigen persistence due to chronic viral infection leads to CD8+ T cell exhaustion.A portion of exhausted CD8+ T cells has the capacity to activate the Tfh program in a Tcf1-dependent manner.Those Tfh-like CD8+ T cells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication.Thus,dissecting the molecular aspects ofT cell identity,during development and immune responses,may lead to new therapies for treating autoimmunity,tumors,and persistent infections.