Postdoc Beth Israel Deaconess Medical Center, Harvard Medical School Malden, Massachusetts, United States
Introduction/Rationale: Systemic lupus erythematosus (SLE) is characterized by impaired regulatory T cell (Treg) function and dysregulated immune metabolism. We previously identified protein phosphatase 2A (PP2A) as a critical regulator of Treg suppressive activity. Emerging evidence suggests that the pentose phosphate pathway (PPP) plays an essential role in immune cell fate decisions.
Methods: Phosphoproteomic and metabolomic analyses were performed on Treg cells from PP2A–wild-type and PP2A-deficient mice. The PPP metabolite gluconolactone (GDL) was evaluated for its effects on CD4⁺ T cell differentiation and Treg suppressive function in murine and human cells in vitro. The therapeutic efficacy of GDL was assessed in vivo using imiquimod-induced dermatitis and spontaneous lupus-prone MRL.lpr mouse models. Finally, the clinical and histologic effects of topical GDL were evaluated in a pilot study of patients with cutaneous lupus erythematosus.
Results: PP2A regulates Treg function through modulation of the PPP. We identified GDL as a key PPP metabolite that enhances induced Treg differentiation and suppressive function while inhibiting T helper 17 (TH17) cell differentiation in murine T cells. In vivo, GDL treatment increased Treg function and significantly ameliorated skin inflammation in both imiquimod-induced and spontaneous lupus mouse models. Ex vivo studies using T cells from patients with SLE demonstrated that GDL similarly promoted Treg differentiation and function. Notably, topical application of a GDL-containing cream in patients with cutaneous lupus erythematosus led to marked clinical and histologic improvement of skin lesions within two weeks
Conclusion: Our findings identify gluconolactone as a metabolite of the pentose phosphate pathway that restores immune regulation by enhancing Treg function and suppressing TH17 responses. GDL represents a promising metabolic-based therapeutic strategy for the treatment of inflammatory and autoimmune diseases.
