One-carbon metabolism upregulated in lupus promotes the differentiation and effector functions of human B and T cells

OBJECTIVES: Systemic lupus erythematosus (SLE) is a multi-organ inflammatory disease driven by autoreactive B and T cells. The serine, glycine, and one‑carbon (SGOC) network controls the proliferation and effector functions of mouse B and T cells; however, its roles in human lymphocytes and SLE are largely unknown. We hypothesize that this network is upregulated in SLE and regulates the functions of human B and T cells. METHODS: We employed RT-qPCR and single-cell RNA-seq to analyze SGOC expression in B and T cells from SLE patients and healthy controls. The proliferation of human B and T cells, plasma cell differentiation, cytokine production of CD4 T cells with or without the SGOC inhibitors in ex vivo culture systems were evaluated using flow cytometry. Antibody secretion was assessed by ELISA. RESULTS: RT-qPCR data reveal MTHFD2 upregulation in B cells from SLE patients. Single‑cell RNA‑seq demonstrated increased expression of PHGDH, PSAT1, SHMT1, SHMT2, and MTHFD2 in B‑cell subsets from patients with active SLE. Inhibiting the SGOC network reduced the proliferation of human B cells, CD4 T cells, and CD8 T cells, and impaired plasma cell differentiation and antibody production. Inhibiting one-carbon (1C) metabolism in this network blocked IFN‑γ production, whereas PHGDH inhibitor reduced IL‑17A production by CD4 T cells. CONCLUSION: The SGOC network, particularly MTHFD2, was upregulated in SLE B cells. The 1C metabolism critically promoted the proliferation and effector functions of human B and T cells, suggesting that 1C metabolism could be a promising new therapeutic target for SLE.