IL-2 signalling sustains pathogenic age-associated B cell homeostasis in lupus

Despite expanding regulatory T (Treg) cells, low-dose interleukin-2 (IL-2) therapy shows variable clinical efficacy in systemic lupus erythematosus (SLE). Here, we investigated whether previously unrecognised effects of IL-2 on age-associated B cells (ABCs) explain this therapeutic heterogeneity. Integrated transcriptomic analysis was used to identify the prevalent signalling pathways associated with lupus pathogenic ABCs. The effects of IL-2 on ABCs were examined. TLR7-driven lupus-prone mice were administered to assess the efficacy of IL-2 therapy. IL-2 responsiveness of ABC was further evaluated in patients with SLE through bioinformatic analysis. Transcriptomic and single-cell analyses revealed elevated IL-2 signalling in ABCs, with a more pronounced IL-2 signature in patients with SLE than in healthy controls. IL2RB, a subunit of the IL-2 receptor, was significantly enriched in ABCs and showed increased chromatin accessibility at its promoter. IL-2 promoted ABC survival and differentiation in a stage-dependent manner. Prior IL-2 administration to recipient mice promoted the persistence of adoptively transferred ABCs. In lupus-prone mice, IL-2 administration increased both ABC and Treg populations without ameliorating disease manifestations with ABC's promotion being more dependent on the disease condition. Additionally, ABCs showed elevated expression of IL-2 receptor correlating with ABC frequency in our cohorts, and activation of IL-2 signalling was further observed in B cells and ABCs from patients with SLE. This study identified ABCs as a novel target of IL-2, expanding the understanding of IL-2's role in SLE beyond the traditional Treg-centric view and offering insights into the variable therapeutic efficacy of IL-2 in this context.