Insulin Sensitivity Controls Activity of Pathogenic CD4+T Cells in Rheumatoid Arthritis

Hyperinsulinemia connects obesity, and a poor lipid profile, with type 2 diabetes (T2D). Here, we investigated consequences of insulin exposure for T cell function in the canonical autoimmunity of rheumatoid arthritis (RA). We observed that insulin levels correlated with the glycolytic index of CD4+ cells but suppressed transcription of insulin receptor substrates, which was inversely related to insulin sensitivity. This connection between insulin levels and the glycolytic index was not seen in CD4+ cells of healthy controls. Exposure of CD4+ cells to insulin induced a senescent state recognized by cell cycle arrest and DNA content enrichment measured by flow cytometry. It also resulted in accumulation of DNA damage marker gamma H2AX. Insulin suppressed IFN gamma production and induced the senescence-associated secretome in CD4+ cell cultures and in patients with hyperinsulinemia. Inhibition of JAK-STAT signaling (JAKi) improved insulin signaling, which activated the glycolytic index and facilitated senescence in CD4+ cell cultures. Treatment with JAKi was associated with an abundance of na & iuml;ve and recent thymic emigrant T cells in the circulation of RA patients. Thus, we concluded that insulin exerts immunosuppressive ability by inducing senescence and inhibiting IFN gamma production in CD4+ cells. JAKi promotes insulin effects and supports elimination of the pathogenic CD4+ cell in RA patients.