Twist2 promotes CD8⁺ T-cell differentiation by repressing ThPOK expression

CD4/CD8 T-cell lineage differentiation is a key process in immune system development; however, a defined regulator(s) that converts the signal from T-cell receptor and co-receptor complexes into lineage differentiation remains unclear. Here, we show that Twist2 is a critical factor in CD4/CD8 thymocyte differentiation. Twist2 expression is differentially regulated by T-cell receptor signaling, leading to differentiation into the CD4 or CD8 lineage. Forced Twist2 expression perturbed CD4⁺ thymocyte differentiation while enhancing CD8⁺ thymocyte differentiation. Furthermore, Twist2 expression produced mature CD8⁺ thymocytes in B₂m^-/- mice, while its deficiency significantly impaired CD8⁺ cells in MHC class-II^-/- and TCR transgenic mice, favoring CD8 T-cell differentiation. During CD8 lineage differentiation, Twist2 interacted with Runx3 to bind to the silencer region of the ThPOK locus, thereby blocking ThPOK expression. These findings indicate that Twist2 is a part of the transcription factor network controlling CD8 lineage differentiation.