Background: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease, characterized by defects in the immune response and the generation of a variety of autoantibodies including anti-dsDNA antibody, causing damage in various organs including kidney, skin and others[1,2]. T cells play a central role in the immunopathogenesis of SLE, contributing to aberrant B cells help, proinflammatory cytokine production, and sustained tissue inflammation. Extensive studies have revealed abnormalities in T cell activation, differentiation, and signaling in SLE[3–6]. Glucocorticoid-induced tumor necrosis factor receptor (GITR, also known as TNFRSF18) is a co-stimulatory receptor enriched on Treg cells and induced on activated T cells, while its ligand (GITRL) is primarily expressed on antigen-presenting cells (APCs), including monocytes and dendritic cells (DCs)[7-9].Mesenchymal stromal cells (MSCs) transplantation (MSCT) has emerged over the past two decades as a promising therapeutic strategy for refractory SLE, with multiple clinical studies—including those from our group—demonstrating improved disease activity and reduced autoantibody levels following MSCs infusion[10,11]. MSCs exert broad immunoregulatory effects through secretion of soluble mediators and cell-cell interactions, influencing multiple immune cells types including DCs, macrophages, and T cells[12,13].

Objectives: GITR and GITRL in SLE and evaluated whether MSCs restore immune homeostasis by targeting this pathway.

Methods: Co-stimulatory receptors and ligands were analyzed in peripheral blood from SLE patients and healthy controls. GITRL expression was examined in isolated monocytes. The functional impact of GITRL-GITR signaling on Th1, Th17, and Treg differentiation was assessed in vitro and in MRL/lpr lupus mice. Monocytes and PBMCs from patients were co-cultured with MSCs to evaluate their regulatory effects. Pathway and T cell subset changes were analyzed following MSC transplantation in patients and mice.

Results: CD4 ⁺ T cells from SLE patients showed elevated GITR, while monocytes were the primary source of upregulated GITRL. Increased GITRL-GITR signaling correlated with disease activity, promoted Th1/Th17 differentiation, and suppressed Treg development. MSCs suppressed GITRL expression on monocytes and reduced GITR on CD4 ⁺ T cells, thereby rebalancing T cell subsets in vitro and in vivo. Mechanistically, MSC-derived hepatocyte growth factor (HGF) inhibited NF-κB activation in monocytes, leading to reduced GITRL expression and attenuated immune activation.

Conclusions: MSCs mitigate pathogenic GITRL-GITR engagement by suppressing monocyte-derived GITRL via HGF-mediated inhibition of the NF-κB pathway, restoring T cell balance and ameliorating SLE.

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Acknowledgments: NIL.

Disclosure of Interests: None declared.