The Role Of CRL4^DCAF2 In T Cell Proliferation And The T Cell-mediated Autoimmune Disease

T lymphocytes play an important role in adaptive immune system of mammals.The proliferation disorder or dysfuntion of T lymphocytes lead to a serious immunedeficiency disease?IDD?or autoimmune disease?AID?.Inflammatory Bowel Disease?IBD?,including Ulcerative Colitis?UC?and Crohn's Disease?CD?,is generally regarded as a type of AID mediated by T cell.By analyzing the PBMCs samples,we found that DCAF2exprssion is higher in PBMCs from IBD patients than that in healthy donors.Our data also show the tight correlation between DCAF2 expression and the activated state of T cells,characterized by DCAF2 increment induced by TCR signaling.Our study revealed the physiological function of E3 ubiquitin ligase CRL4^DCAF2 in T cells that has not been clarified before.Due to the embryonic legthality of DCAF2 deficient mice,we generate a mice specific knoukout DCAF2 in T cells?TKO?.The TKO mice show the relief of AID symptoms comparing to those in WT littermates.To investigate the role and underlying mechanism of DCAF2 defect in regulating the T cells,we analyse the development and maintenance of immune system in TKO mice.Interestingly,the DCAF2 deficiency causes the defect of peripheral T cells maintenance,but displayed no effects on T cell development.The data further revealed this defect was due to the reduction in the proliferation capacity of peripheral T cells,other than to migration capacity.Additionally,we observed that the DCAF2-deficient T cells displayed a M phase arrest which is not caused by the impairment of IL-2 or the increase in p53/p21.Finally,we demonstrated that DCAF2 deficiency disrupted the demethylation of H4K20,which led to the dowregulation of Aurora B.Aurora B is critical for the 26S proteasome activity,thus the decreased activity of 26S proteasome leads to the M phase arrest.Our study has clarified the function and its mechanism of the CRL4^DCAF2 in T cells and suggests that DCAF2 could be used as a therapeutic target for T cell-mediated autoimmune disease.