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 B 2 m −/− 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.