Role Of SENP1 In Regulating CD4~+ T Cells Activation And Differentiation

The adaptive immunity induced by CD4⁺T cells play a critical role in anti-microbial infection,antitumor immunity and inflammation.Dysfunction of CD4⁺T cell immune response is associated with the development of tumor and inflammatory diseases.Therefore,the activation and differentiation of CD4⁺T cells need to be tightly regulated to maintain immune homeostasis.Recent studies have shown that several post-translational modifications（PTMs）,such as phosphorylation,ubiquitination and methylation,are involved in regulating TCR-proximal signaling and T cell differentiation process.Whether SUMOylation plays a role in T cell activation and differentiation remains largely unknown.SUMOylation is a kind of ubiquitin-like modification.It functions as an important regulatory mechanism in multiple physiological and pathological processes by changing the location and activity of the substrates or interacting with other proteins.SUMO modification is a dynamic process,which is catalyzed by SUMO-specific ligases and removed by SUMO-specific proteases（SENPs）.In our preliminary studies,we found that SENP1 was dynamically expressed during CD4⁺T cell activation and differentiation.Hense,we postulated that SENP1 might regulate CD4⁺T cell activatiaon and differentiatiaon.To test this hypothesis,we intercrossed floxed SENP1(Senp1^f/f)mice with CD4-Cre line to generate T cell specific SENP1-knockout mice.Compared with wide type control mice,we found that SENP1 deficiency promoted Th1differentiation in vivo and in vitro.SENP1 deficiency resulted in spontaneous auto-inflammation in multiple organs of aging mice,as indicated by infiltration of large number of mononuclear cells and elevated Th1 response.Futher,we utilized the colitis model by adoptive transfer of CD4⁺CD45RB^high T cells to verify SENP1 deficiency promoting Th1 response and tissue inflammation.We found that SENP1-deficient CD4⁺cells promoted colitis with increased Th1 responses.Through RNA-seq analysis,we found gene clusters associated with glycolysis and NFAT signature were enriched in SENP1-deficient Th1 cells.These data suggested that SENP1 might regulate Th1differentiation through regulating glycolysis process controlled by NFAT2.Subsequently,we found that NFAT2 was specifically DeSUMOylated by SENP1 and de-SUMOylation of NFAT2 led to inhibition of its transcriotional activity to suppress the expression of glycolysis-associated genes in vitro.Collectively,our studies show that SENP1,which was up-regulated in CD4⁺T cells upon TCR activation,negatively controls the transcription activity of NFAT2 through deSUMOylation to reduce the rate of glycolysis and therefore to prevent Th1 overactivation.