Abstract
Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH 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 TFH 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.
Highlights
CD4+ T cells have a vital role in adaptive immune responses and can differentiate into functionally distinct subsets, including effector helper T cells (type 1 helper T cells (Th1), Th2, Th17, TFH) or regulatory T cells (Treg), triggered by environmental cytokine milieu
We further revealed that Ddb[1] ablation led to accumulation of DNA damage, cell cycle arrest, and increase of cell death, thereby resulting in the defect of TFH and Th1 cell expansion
Naïve CD4+ T cells were isolated from spleens and lymph nodes of 8-week-old WT and Ddb1fl/fl; OX40-cre mice, and cells were co-cultured with Antigen Presenting Cells (APC cells) in 96-well U bottom plate with soluble 1 mg/ml antimouse CD3 and 1 mg/ml anti-mouse CD28 antibodies
Summary
CD4+ T cells have a vital role in adaptive immune responses and can differentiate into functionally distinct subsets, including effector helper T cells (type 1 helper T cells (Th1), Th2, Th17, TFH) or regulatory T cells (Treg), triggered by environmental cytokine milieu. Current understanding suggests that activation-induced Tcell cycle progression and T-cell death are crucial for T-cell mediated immune responses. T-cell expansion and T-cell death were tightly controlled by multiple regulatory checkpoints One of these is G2/M DNA damage checkpoint that prevents rapidly proliferating cells from entering mitosis (M-phase) with unrepaired DNA damage induced by DNA replication stress. We further revealed that Ddb[1] ablation led to accumulation of DNA damage, cell cycle arrest, and increase of cell death, thereby resulting in the defect of TFH and Th1 cell expansion. Our study demonstrates that Ddb[1] is an essential positive regulator of CD4+ helper T-cell expansion, including TFH and Th1 cells
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