Ddb1 Is Essential For Effector CD4~+ T Cells By Regulating Cell Cycle Progression And Cell Death

The immune system is a remarkably versatile defense system that has evolved to protect animals from invading pathogenic microorganisms.Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity.The T cells and B cells are critical components of the adaptive immune system.T lymphocytes(T cells)including CD4+T cells and CD8+T cells have a vital role in adaptive immune responses.CD4+T cells can provide assistance for other cells in the immune response(T help cells including Thl,Th2,Th7,TFH cells and so on).CD8+T cells have anti-tumor and anti-viral microbial effects by the secretion of cytokines including IFNγ and TNFa.The proper function of CD4+T cells and CD8+T cells are vital for immune homeostasis.Damage DNA binding protein 1(Ddb1)was originally identified as a protein heterodimerizes with Ddb2 as UV-DDB complex,and the complex of UV-DDB was involved in the NER(Nucleotide Excision Repair)pathway.More research suggested Ddb1 can act as a component of the Ddb1-Cul4-DCAFs E3 ligase complex and target various substrates for ubiquitination in diverse cellular functions.Many studies have investigated how Ddb1 regulates embryonic development and CNS(Central Nervous System)development,however little is known about how Ddb1 regulates the function of T cells,especially in effector CD4+T cells.To investigate the role of Ddb1 in T-cell function,we inactivated the DDB1 gene in T cells at different development stages by CD4-cre and OX40-cre.In Ddb1fl/fl;CD4-cre mice,we found that the deletion of Ddb1 slightly impaired the development of T cells,and Ddb1fl/fl;CD4-cre mice showed various immune disorders after LCMV A4 infection including the defect of CD8+T cells,Thl cells,TFH cells and B cells response.To further explore the role of Ddb1 in effector CD4+T cells,we analyzed the immune response of Ddb1fl/fl;OX40-cre mice and found that deletion of Ddb1 resulted in TFH cell and germinal center response defect to acute viral infection by regulating effector CD4+T cell expansion.Mechanistically,Ddb1 deficiency in effector CD4+T cells resulted in the abnormal accumulation of p53,the accumulation of p53 in effector CD4+ T cells led to cell proliferation defect and increase of cell death.Beyond that,Ddb1 deficiency in effector CD4+T cells resulted in the accumulation of DNA damage and the activation of ATM/ATR-Chkl cell cycle check point.Cell cycle of Ddb1 deficient effector CD4+T cells blocked in G2-M phase and underwent rapid cell death,eventually caused the defect of CD4+T cell differentiation and function.Therefore,our study demonstrated that Ddb1 acts as an essential positive regulator in T cell function especially in effector CD4+T cell immune response to acute viral infection.