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Objectives: To investigate the differentiation of regulatory T cells (Tregs) induced by methylprednisolone (MP) pulse therapy in patients with Systemic Lupus Erythematosus (SLE)., Methods: We enrolled 30 patients with SLE and analyzed peripheral blood mononuclear cells (PBMCs) before and after MP pulse therapy. Peripheral Tregs, apoptosis of PBMCs subsets, and TGFβ production by monocytes was quantified by flow cytometry. Proliferation and IFN-γ production of CD4 + T cells were measured. Furthermore, TGFβ1 production by human monocyte-derived macrophages (HMDM) stimulated with MP-treated CD4 + T cells were quantified by ELISA., Results: Peripheral Tregs was significantly increased after MP pulse therapy (6.76 ± 1.46% vs. 3.82 ± 1.02%, p < 0.01), with an expansion of Nrp1 - induced Tregs (4.54 ± 0.46% vs. 1.75 ± 0.38%, p < 0.01). Proliferation and IFN-γ production of CD4 + T cells were significantly decreased after MP pulse therapy. MP pulse therapy induced CD4 + T cell apoptosis (early apoptosis, 26.34 ± 3.54% vs. 14.81 ± 2.89%, p < 0.01) and TGFβ expression on monocytes (6.02% vs. 2.45%, p < 0.01). Furthermore, MP induced CD4 + T cell apoptosis in vitro, which stimulated HMDM to produce TGFβ. Moreover, elevated TGFβ level in supernatant from HMDM stimulated with MP-treated CD4 + T cells promoted Tregs differentiation., Conclusions: MP pulse therapy induces CD4 + T cell apoptosis, which promotes monocytes to produce TGFβ and further facilitates Tregs differentiation. Newly-differentiated Tregs suppress proliferation and IFN-γ production of CD4 + T cells and contribute to immunoregulatory milieu after MP pulse therapy., (Copyright © 2022. Published by Elsevier Inc.)