Metabolic Reprogramming of T Cells by MSCs Rebalances Th17/Treg Axis to Attenuate Collagen-Induced Arthritis.

BACKGROUND

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by dysregulated T cell responses and metabolic disturbances. Mesenchymal stromal cells (MSCs) have shown therapeutic promise, but their mechanisms, particularly concerning T cell metabolism, remain incompletely defined. This study investigated whether human umbilical cord-derived MSCs (hUC-MSCs) ameliorate collagen-induced arthritis (CIA) by modulating T cell metabolism and differentiation.

METHODS

CIA was induced in DBA/1 mice. Animals received PBS or hUC-MSCs on day 28. Arthritis index (AI), joint histology, serum cytokines (TNF-α, IL-6, IL-17, and TGF-β), and metabolites (lactate and pyruvate) were assessed. Splenic T cell transcription factors (FOXP3, RORγt, and PU.1) and glycolytic genes (GLUT1, G6PD, and PFKFB3) were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. In vitro, human CD4+ T cells were cocultured with hUC-MSCs under T-helper 17 (Th17)-polarizing conditions. T cell subsets, glycolytic metabolites, and gene/protein expression were evaluated by flow cytometry, colorimetric assays, RT-qPCR, and western blot.

RESULTS

MSC treatment significantly attenuated arthritis severity, joint destruction, and splenomegaly in CIA mice. It reduced serum pro-inflammatory cytokines and normalized elevated lactate and pyruvate levels. In the spleen, MSCs suppressed RORγt and PU.1 while enhancing FOXP3 expression, and downregulated GLUT1 and G6PD mRNA. Positive correlations were found between glycolytic markers (GLUT1 and G6PD) and pro-inflammatory transcription factors (RORγt and PU.1), and between serum lactate and inflammatory cytokines. In vitro, hUC-MSCs directly inhibited Th17 differentiation and promoted Treg generation in human CD4+ T cells. This metabolic reprogramming was functionally coupled to a shift in T cell differentiation: a suppression of pro-inflammatory Th17 cells and a promotion of regulatory T (Treg) generation in human CD4+ T cells. This was accompanied by reduced lactate production and significant downregulation of GLUT1, G6PD, and PFKFB3 at both mRNA and protein levels.

CONCLUSIONS

hUC-MSCs ameliorate CIA by restoring the Th17/Treg balance through metabolic reprogramming of T cells, specifically by suppressing glycolysis. This immunometabolic mechanism highlights the therapeutic potential of MSCs in RA.