Leptin Upregulates Peripheral CD4 + CXCR5 + ICOS + T Cells via Increased IL-6 in Rheumatoid Arthritis Patients

CD4⁺CXCR5⁺ICOS⁺ T cells, known as Tfh (T Follicular helper) cells, are required for antibody production. Abnormal production and differentiation of Tfh cells are involved in many autoimmune diseases, including rheumatoid arthritis (RA). Leptin has the property of modulating immune system. Here, we explored the effect of leptin on CD4⁺CXCR5⁺ICOS⁺ T cells production in RA patients. Serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cells (PBMC) stimulated with CD3/CD28 were cultured in the presence and absence of leptin and with or without anti-IL-6 receptor (anti-IL-6R), anti-IL-21R, and anti-IL-12R antibody respectively. IL-6, IL-21, and IL-12 levels were determined by ELISA. Bcl-6 was detected by reverse transcription-polymerase chain reaction. STAT1, pSTAT1, STAT3, and pSTAT3 were examined by western blot. We found that leptin levels were higher in RA patients than healthy controls. Leptin-stimulated RA PBMC upregulated CD4⁺CXCR5⁺ICOS⁺ T cells, along with increased IL-6, IL-21, and IL-12.CD4⁺CXCR5⁺ICOS⁺ T cells, Bcl-6 mRNA expression, pSTAT1, and pSTAT3 obviously declined when anti-IL-6R antibody was added into leptin-treated RA PBMC, which suggested that leptin upregulated RA CD4⁺CXCR5⁺ICOS⁺ T cells via increased IL-6 by activation of STAT1 and STAT3. We presented an innovative mechanism on how leptin participated in RA pathogenesis.