The Molecular Mechanism Through Which TIPE2 Regulates The Thymus Egress Of Regulatory T Cells And The Polarization Of M2 Macrophages

Regulatory T cells and M2 macrophages play important roles in the regulation of the innate and adaptive immune responses and maintain the immune homeostasis.Tumor necrosis factor-? induced protein-8-like 2(TIPE2)belongs to TNFAIP8 family and is a negative regulator of innate and adaptive immune response.Previous studies showed that TIPE2 alleviates experimental systemic lupus erythematosus through induction of macrophage polarization to an M2 phenotype.Besides,it was reported that expression of TIPE2 contributes to the immunosuppressive property of regulatory T cells.However,the underlying molecular mechanism remains unclear.In the current study,I investigated the role of TIPE2 in Treg biology and M2 macrophage polarization using TIPE2-deficient mice.Major results of the current study were summarized as follows:1.TIPE2 is required for the thymus egress of tTregs but not the development and apoptosis of tTreg.Previous studies indicate that TIPE2 is required for the expression of Treg signature genes and promotes leading-edge formation in neutrophils through cytoskeleton remodeling.In the current study,we showed that TIPE2 deficient mice accumulate more Treg cells in the thymus.Further studies revealed that TIPE2 deficiency doesn't affect the development and apoptosis of tTregs.Instead,TIPE2 promotes the chemotaxis of tTregs in vitro,which may account for the accumulation of Tregs in the thymus of TIPE2 deficient mice.Mechanistic study revealed that TIPE2 promotes the polarization of pAKT and F-actin in tTregs undergoing directed migration.Taken together,these results demonstrated that TIPE2 enhances the cytoskeleton remodeling and promotes the thymus egress of tTregs,which may play an important role in the maintenance of self-tolerance.2.TIPE2 Promotes M2 Macrophage Polarization through the Activation of PI3K-AKT Signaling.TIPE2 deficient bone-marrow cells were found to be defective in IL-4 induced M2 macrophage differentiation in vitro.Mechanistic studies revealed that TIPE2 promotes phosphoinositide metabolism and the activation of the downstream AKT signaling pathway,which leads to the expression of markers specific for M2 macrophages.Furthermore,Tipe2-deficiency does not affect the activation of the JAK-STAT6 signaling pathway which also plays an important role in M2 macrophage differentiation.Conclusively,these results indicate that TIPE2 is required for the thymus egress of tTregs,and the promotion of M2 macrophage differentiation through the activation of PI3K-AKT signaling pathway,hence,emphasizing the important role that TIPE2 plays in the maintenance of immune hemostasis.