Ddb1 Is Essential for the Expansion of CD4⁺ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

Follicular helper T (T_FH) cells are specialized CD4⁺ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of T_FH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4⁺ helper T cells including T_FH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4⁺ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4⁺ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4⁺ helper T cells.