The Effects Of PD-1 Ubiquitination Modification On Treg Cell Function

As an important immunosuppressive receptor,PD-1 is highly expressed on the surface of immune cell membrane in tumor microenvironment and inhibits the function of immune cells by interacting with the ligand PD-L1 on tumor cells.At present,there are several antibodies targeting the PD-1/PD-L1 pathway in clinical practice,which have good efficacy against melanoma,non-small cell lung cancer and other tumors.However,PD-1 not only plays an important role in anti-tumor immunity,but also plays an important role in immune tolerance of the body.Regulatory T cells(Treg cells)are one of the important factors in maintaining immune tolerance.Therefore,both Treg cells and PD-1 molecule play an important role in maintaining immune tolerance.Meanwhile,Treg cells constitutively expressed PD-1 molecule.As far as current studies are concerned,how the functions of Treg cells will change when the PD-1 signaling pathway of Treg cells is activated is still controversial.Previous studies have found that PD-1 can undergo ubiquitination degradation and identified a key E3 ligase FBX038 that catalyzed PD-1 ubiquitination modification and degradation through the proteasome pathway.Based on previous studies,in the process of raising Fbxo38f/fCD4Cre conditional knockout mice,it was found that the body weight of 12-month-old Fbxo38f/fCD4Cre male mice was significantly lower than that of the control group,accompanied by enteritis caused by abnormal infiltration of immune cells.Previous studies have shown that Treg cells and Th17 cells play an important role in the occurrence and development of inflammatory enteritis.In contrast to Treg cells,Th 17 cells can promote inflammation by secreting a variety of cytokines,such as IL-17.For Th17 cells,the PD-1 pathway may inhibit IL-17 secretion.In the context of Fbxo38f/fCD4Cre conditional knockout mice,the knockout of Fbxo38 may result in upregulation of PD-1 in Th17 cells,which may inhibit the pro-inflammatory function of Th17 cells.Based on this,we hypothesized that the enteritis phenotype of Fbxo38f/fCD4Cre conditional knockout mice at 12 months of age might be related to Treg cells rather than Th17 cells.Therefore,this study focuses on the influence of Treg cells on the occurrence and development of enteritis.This study took enteritis as the starting point.Firstly,we found that Fbxo38 specific knockout did not affect the development and differentiation of Treg cells,and Fbxo38 specific knockout did not affect the differentiation of iTreg cells.Then,we used the classical Treg cell inhibition experiment in vitro to study the difference in immunosuppressive function of spleen Treg cells in 12-month-old Fbxo38f/fCD4Cre mice and Fbxo38f/f mice,and found that the immunosuppressive function of Treg cells in conditioned knockout mice was inhibited.It was preliminarily revealed that the occurrence of enteritis in conditioned knockout mice may be related to the inhibition of Treg cell function.Subsequently,the PD-1 expression level of intestinal Treg cells in 12-month-old conditional knockout mice and control mice was further studied,and the results showed that the PD-1 expression level of intestinal Treg cells in 12-month-old conditional knockout mice was significantly higher than that in the control group.It was preliminarily suggested that PD-1 signaling pathway might influence Treg cell function.This study primarily revealed the influence of PD-1 pathway on Treg cell function from the perspective of PD-1 stability,and provided a new mechanism of enteritis.