Abstract / Summary
Aberrant CD4⁺ T cell differentiation, particularly the expansion of T follicular helper (Tfh) cells, is a hallmark of systemic lupus erythematosus (SLE) and is critically dependent on metabolic reprogramming. Although altered lactate metabolism has been implicated in autoimmune disorders, how lactate influences Tfh cell differentiation and contributes to SLE pathogenesis remains poorly understood. Clinical associations were examined in SLE patient cohorts and lupus‑prone MRL/ lpr mice. In vitro Tfh cell differentiation assays, in vivo autoimmune models (SRBC immunization and bm12‑induced chronic graft‑versus‑host disease, cGVHD), glycolytic flux measurements, and epigenomic analyses focusing on histone lactylation were performed to dissect the underlying mechanisms. Serum lactate levels were significantly reduced in SLE patients and lupus‑prone mice and inversely correlated with disease activity. Exogenous lactate suppressed Tfh cell differentiation in vitro and attenuated Tfh‑mediated autoimmune pathology in vivo. Tfh polarization was associated with increased glycolytic activity and elevated histone H3 lysine 18 lactylation (H3K18la). Under Tfh-polarizing conditions, lactate treatment was associated with reduced glucose utilization, glycolytic capacity, H3K18la levels, and H3K18la enrichment at promoters of Tfh-associated genes. In contrast, under non-polarizing conditions, lactate increased H3K18la and promoted a Tfh-like phenotype, supporting a cellular-state-dependent effect. H3K18la levels were elevated in total CD4⁺ T cells and flow cytometry-gated circulating Tfh cells from patients with SLE. In the bm12-cGVHD lupus-like model, sodium lactate (NaLac) administration attenuated autoantibody production, renal injury, and pathogenic immune-cell responses, concomitant with reduced H3K18la in splenic CD4⁺ T cells. These findings support a context-dependent role for lactate-related metabolic and H3K18la remodeling in the regulation of Tfh-cell responses and lupus-like immune pathology. Lactate-associated metabolic-epigenetic pathways warrant further investigation as potential therapeutic targets in SLE and related autoimmune diseases.