The Mechanisms Of Protein Phosphatase 6 Regulating The Development And Function Of Regulatory T Cells

Protein phosphatase 6 is a Ser/Thr protein phosphatase that plays an important role in a variety of physiological and pathological processes.Two published papers of our lab in 2015 have showed that microRNA-31 can regulate psoriasis by directly targeting and inhibiting the expression of protein phosphatase 6.MicroRNA-31 knock out can effectively alleviate EAE by promoting Treg differentiation.A recent study carried out by our collaborator Qun Li,an associate professor at Shanghai Institute of Hypertension,has found that microRNA-31 can promote hypertension development by inhibting the differentiation of regulatory T cells.To explore wheather Protein phosphatase 6 can regulate the course of hypertension by acting on Treg,we did further study with the associate professor Qun Li by inducing a hypertension mouse model with Ang?in cKO mice which delete Protein phosphatase 6 specifically in Treg.The result showed that the blood pressure increase and tissue damage degree of target organs from cKO mice were both significantly higher than that of the control group.We further found the proportion of Treg cells decreased and the infiltration of inflammatory cells increased in the target organs from cKO hypertension mice.These results suggest that Treg differentiation and suppressive function are both abnormal in absence of protein phosphatase 6,thus leading to hypertension aggravation.In addition,we also found that Protein phosphatase 6 cKO mice spontaneously developed inflammatory disease,and they can also be induced severe EAE.Besides,the percentage of cKO Treg was also decreased in the EAE model.We conducted the following series studies to find out how protein phosphatase 6 regulates the differentiation and immunosuppressive function of Treg cells.The results showed that the in vitro differentiation of cKO iTreg was seriously impaired.And the adaptive transfer colitis model showed that the immunosuppressive function of iTreg from cKO mice were also badly damaged.As the most important transcription factor of Treg,FoxP3 plays an important role in maintaining normal differentiation and immunosuppressive function of Treg cells.We found the expression of FoxP3 and its target protein CD25 were both significantly decreased in Treg cells from cKO mice.Besides,as an important transcription factor of foxp3,the phosphorylation of STAT5 were decreased in cKO Treg cells.As the trancription factor of other proteins,STAT3 can also bind to the promoter regions of foxp3 to compete for the binding sites of p-STAT5,thus inhibiting the expression of FoxP3.We further treated iTreg with p-STAT3 inhibitor during their differentiation in vitro,and found the expression of FoxP3 and the differentiation ratio of Treg were all upregulated in both groups,but the cKO group increase more and reached the level of control group.The results above suggest that protein phosphatase 6 in Treg cells may promote the expression of FoxP3 and CD25 by inhibiting the phosphorylation of STAT3 at tyrosine 705 to maintain its normal development.On the other hand,the increased expression of CD25 also enhanced the ability of Treg to compete for IL-2,and promoted its immunosuppressive function.To sum up,we believe that protein phosphatase 6 may regulate the development and immunosuppressive function of Treg cells through above mechanisms,thereby influencing the development of related diseases like hypertension.