Sustained low‐dose interleukin‐2 therapy alleviates pathogenic humoral immunity via elevating the Tfr/Tfh ratio in lupus

Objectives Low‐dose interleukin‐2 (IL‐2) has shown promising clinical benefits in the treatment of systemic lupus erythematosus (SLE), but how this therapy alleviates pathogenic humoral immunity remains not well understood. The dilemma is that IL‐2 can suppress both follicular helper and regulatory T (Tfh and Tfr) cells, which counteract each other in regulating autoantibody production. Methods Female NZB/W F1 mice received recombinant human IL‐2 (3 × 104 IU/dose) in three treatment regimens: (1) short, daily for 7 days; (2) medium, daily for 14 days, and (3) long, every second day for 28 days. Tfh (Foxp3−CXCR5+Bcl6+), Tfr (Foxp3+CXCR5+Bcl6+), germinal centre (GC, B220+GL‐7+Fas+) and antibody‐secreting cell (ASC, B220−CD138+TACI+) were analysed by flow cytometry. Serum anti‐dsDNA level was determined by ELISA. Kidney pathology was evaluated by H&E and immunofluorescence staining. Circulating Tfh and Tfr cells in SLE patients treated with low‐dose IL‐2 from a previous clinical trial (NCT02084238) was analysed. Results Low‐dose IL‐2 treatment consistently increased Tfr/Tfh ratio in mice and SLE patients, because of a stronger suppression on Tfh cells than Tfr cells. Three treatment regimens revealed distinct immunological features. Tfh suppression was observed in all regimens, but Tfr suppression and GC reduction were recorded in just medium and long regimens. Only the long treatment regimen resulted in inhibited ASC differentiation in spleen, which was accompanied by reduced anti‐dsDNA titres and ameliorated kidney pathology. Conclusion Low‐dose IL‐2 therapy increases the Tfr/Tfh ratio, and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function. We designed and examined three treatment regimens of low‐dose interleukin‐2 (IL‐2) therapy in lupus‐prone NZB/W F1 mice and characterised the immune responses in detail. Low‐dose IL‐2 therapy increases the Tfr/Tfh ratio and a less frequent and prolonged treatment can alleviate pathogenic humoral immunity and improve renal function, which provide necessary rationale and new insights in optimising low‐dose IL‐2 therapy.