Insulin enables acquisition of the IL7R⁺ memory phenotype in PD1⁺ T cells in RA tissues

Insulin signaling regulates cellular metabolism in an epigenetic manner, but its role in the immune cell homeostasis remains unknown. High plasma insulin obstructs efficient insulin signaling and rewires metabolic activity in autoimmunity. In this study, we explored the functional consequences of insulin signaling for the metabolism and phenotype of effector CD4⁺ T cells in blood and synovial tissue of patients with rheumatoid arthritis (RA). Transcriptome profiling of CD4⁺ cells in RA blood and synovia revealed high metabolic activity and effector function of the survivin/BIRC5^hiPD1^hi T peripheral helper cell population. Low insulin signaling and deficient histone acetylation in RA T cells amplified proinflammatory IFNγ and TNF expression. Co-deposition of survivin with acetylated histone H3K27 on regulatory chromatin controlled the transcription of histone acetylation complex subunits and insulin-dependent genes. Insulin stimulation and histone deacetylase inhibition induced an increase in histone acetylation. In CD4⁺ cell cultures and in aggressive PD1^hiTph cells in RA synovial tissue, exposure to insulin synergized with inhibition of histone deacetylation to upregulate IL7 production suppressing IFNγ and PD1. This activated IL7R-signaling mediators STAT5A/B, BCL2, and promoted acquisition of CD27⁺CD45RO⁺ central memory phenotype in the PD1^hiTph cells. Likewise, the CD4⁺ cells in hyperinsulinemic T2D patients showed enrichment of IL7R⁺T cell cluster. In RA patients, antagonizing folate transport and JAK/STAT signaling activated insulin signaling and histone acetylation-dependent metabolism of CD4⁺ cells. Concomitant with CTLA4-dependent signaling, this enabled the adoption of an incipient IL7R⁺ T cell phenotype. This study demonstrates that insulin binds together metabolic activity and histone acetylation in CD4⁺ cells. Sufficient insulin signaling promotes IL7R⁺ memory phenotype accrual in aggressive PD1^hiTph cells. Hence, achieving insulin sensitivity via histone acetylation disarms effector CD4⁺ T cell function and presents an attractive interventional goal to restore immune cell homeostasis in RA.