*Purpose: Erythropoietin (EPO) is not only an erythropoiesis hormone, but also an immune regulatory cytokine. The receptors of EPO, (EPOR)₂ and tissue protective receptor (TPR), mediate EPO’s immune regulation. Our group firstly reported a non-erythropoietic peptide derivant of EPO, cyclic helix B peptide (CHBP), which could inhibit macrophages inflammation and dendritic cells (DCs) maturation. As a kind of innate immune regulatory cell, myeloid-derived suppressor cells (MDSCs) share a common myeloid progenitor with macrophages and DCs. In this study, we investigated the effects on MDSCs differentiation and immunosuppressive function via CHBP induction.

*Methods: MDSC differentiation and function was evaluated with or without CHBP stimulation. To compare the immune regulation difference of M-MDSC with or without CHBP stimulation, murine allo-skin transplant model was established. Signal pathways were detected by western blot, RNA-sequencing and protein array.

*Results: CHBP promoted MDSCs differentiate toward M-MDSCs with enhanced immunosuppressive capability. Infusion of CHBP-induced M-MDSCs significantly prolonged murine skin allograft survival compared to its counterpart without CHBP stimulation. In addition, we found CHBP increased the proportion of CD11b⁺Ly6G^–Ly6C^high CD127⁺ M-MDSCs, which exerted stronger immunosuppressive function compared to CD11b⁺Ly6G^–Ly6C^high CD127^– M-MDSCs. In CHBP induced M-MDSCs, we found that EPOR downstream signal proteins Jak2 and STAT3 were upregulated, which had strong relationship with MDSC function. In addition, CHBP upregulated GATA-binding protein 3 (GATA-3) protein translation level, which was an upstream signal of CD127 and regulator of STAT3. These effects of CHBP could be reversed if Epor was deficient.

*Conclusions: Our novel findings identified a new subset of M-MDSCs with better immunosuppressive capability, which was induced by EPOR-mediated Jak2/GATA3/STAT3 pathway. These results are benefit for CHBP clinical translation and MDSC cell therapy in future.

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