Ikaros degradation by Iberdomide correlates with normalization of cytokines in Th cells of patients with systemic lupus erythematosus

Abstract

Systemic lupus erythematosus is sustained by dysfunctional Th cells that amplify autoreactive B-cell responses. Iberdomide, a cereblon modulator that degrades Ikaros and Aiolos, has shown clinical activity in lupus, yet its T cell–centric mechanism remains incompletely defined. Here, using purified Th cells and a PBMC-based T–B cell activation assay, we asked whether targeted degradation of Ikaros reprograms pathogenic T-cell circuitry and constrains B-cell hyperactivity. At baseline, lupus Th cells exhibited the canonical pattern of diminished IL-2 and TNF-α levels, with enrichment of Th2-associated cytokines and elevated IL-6 and IL-9 levels. Iberdomide restored IL-2 and TNF-α and suppressed Th2-associated cytokines, IL-6, and IL-9 across secreted and single-cell readouts. Although the relative frequency of CXCR5+PD-1+ Tfh-like cells increased, ICOS expression decreased; IL-21 increased numerically but not significantly in total CD4 T cells. In the PBMC-based T–B cell activation assay, iberdomide reduced B-cell recovery, plasmablast-like differentiation, and anti-dsDNA levels. Interdonor variability in cytokine modulation tracked more strongly with Ikaros than Aiolos. These findings show iberdomide alters lupus T-cell cytokine networks and is associated with reduced B-cell responses.