Inducible deletion of Ezh2 in CD4+ T cells inhibits kidney T cell infiltration and prevents interstitial nephritis in MRL/lpr lupus-prone mice

Systemic lupus erythematosus is a remitting relapsing autoimmune disease characterized by autoantibody production and multi-organ involvement. T cell epigenetic dysregulation plays an important role in the pathogenesis of lupus. We have previously demonstrated upregulation of the key epigenetic regulator EZH2 in CD4⁺ T cells isolated from lupus patients. To further investigate the role of EZH2 in the pathogenesis of lupus, we generated a tamoxifen-inducible CD4⁺ T cell <i>Ezh2</i> conditional knockout mouse on the MRL/<i>lpr</i> lupus-prone background. We demonstrate that <i>Ezh2</i> deletion abrogates lupus-like disease and prevents T cell differentiation. Single-cell analysis suggests impaired T cell function and activation of programmed cell death pathways in EZH2-deficient mice. <i>Ezh2</i> deletion in CD4⁺ T cells restricts TCR clonal repertoire and prevents kidney-infiltrating effector CD4⁺ T cell expansion and tubulointerstitial nephritis, which has been linked to end-stage renal disease in patients with lupus nephritis.