Fig. 2

Graded expression of key regulators of T cell differentiation and exhaustion in acute and chronic conditions. A: During acute TCR stimulation, the following factors are highest among Tmem cells and gradually decrease in expression during the process of effector differentiation: TCF-1 [80], BACH2 [77], and FOXO1 [75]. Expression of EOMES [81], RUNX3 [82], and BATF-IRF4 [83, 84] is low among Tmem cells, peaks among early Teff cells and recedes in late Teff cells. Finally, the following factors gradually increase in expression and contribute to effector T cell differentiation: T-BET [85] and BLIMP-1 [86]. B: During chronic TCR stimulation, the following factors are highest among Tpex cells and gradually decrease in expression along the course of exhaustion: TCF-1 [35, 87], TOX [87, 88], and FOXO1 [35, 73, 76]. While TCF-1 remains low, expression of TOX and FOXO1 gradually increases as T cells become terminally exhausted. On the other hand, expression of T-BET [85, 87, 89], BATF-IRF4 [35, 90], and NR4A [91] is at its lowest in Tpex cells and is induced during chronic TCR engagement. While T-BET and BATF-IRF4 expression peaks among intermediate exhausted T cells and subsequently recedes, NR4A expression remains high and peaks at the Tex^term cell stage. Expression of EOMES [87, 89, 92] and BLIMP-1 [93] also peaks at the terminal exhausted stage, but their gradual increase in expression starts later, at the intermediate exhausted stage