Figure 1: T cell development and the stages of TCF-1 implication.

Notch signaling upregulates Tcf7 expression in early ETPs ^35–39. TCF-1 induces the expression of genes encoding transcription factors critical for T cell specification, including Gata3 and Bcl11b. The levels of TCF-1 increases progressively up to the CD4⁺CD8⁺ (DP) stage. In CD4⁺CD8⁺ (DP) thymocytes TCF-1 cooperates with HEB to define their epigenetic landscape and trasncription profile ⁴⁴. Following thymic selection the DP cells become either CD4⁺ or CD8⁺ SP cells. TCF-1 fosters the CD4⁺ T cell fate by promoting Zbtb7b (T_H-POK) expression, and although TCF-1 is not required for commitment to the CD8⁺ T cell lineage it ensures CD8⁺ T cell stability by cooperating with RUNX3 to suppress Cd4 gene expression ⁴⁸. TCF-1 also suppresses Rorc (RORγT) and Il17 expression in DP thymocytes preventing their conversion to CD4⁺ T_H17 and CD8⁺ T_C17 cells ^50,113. After thymic egress CD4⁺ T cells differentiate into T_H subsets. TCF-1 promotes T_FH differentiation by inducing Bcl6 and supressing Prdm1 (BLIMP-1) expression and limits T_H1 differentiation by suppressing Tbx21 (T-bet) expression ^63–65. TCF-1 promotes T_H2 differentiation by directly upregulating Gata3 ⁵⁹. TCF-1 is expressed by stem cell-like CD27⁺ T_H17 cells, which persist in models of MS ⁵⁴. In T_REG cell subsets, TCF-1 cooperates with Foxp3 to limit expression of T cell activation and T_H17 differentiation genes. It also enhances Bcl6 expression to promote T_FR differentiation. CD8⁺ T cells are critical for defense against acute and chronic viral infections and cancers. In acute viral infection TCF-1 is important in driving the development of T_MP and T_MEM cells. Both in acute and chronic LCMV infection downregulation of TCF-1 is needed for the differentiation of T_EFF and T_EX cells. In chronic viral infections and cancer, TCF-1 and BCL-6 support the differentiation and maintenance of T_EX-_STEM cells that express PD-1 and can respond to anti-PD-1 therapy.