Therapeutic Potential of Targeting Tfr/Tfh Cell Balance by Low-Dose-IL-2 in Active SLE: A Post-Hoc Analysis from a Double-Blind RCT Study

Abstract

\n Objective: To investigate the regulation of T follicular regulatory (Tfr) and T follicular (Tfh) cell subtypes by low-dose IL-2 in systemic lupus erythematosus (SLE) in a randomized, double-blind, placebo-controlled clinical trial.Methods: A post-hoc analysis was performed in a randomized cohort of SLE patients (n=60) receiving low-dose IL-2 therapy (n=30) or placebo (n=30), along with standard of care treatment. The primary end point was attainment of SLE responder index-4 (SRI-4) at week 12 in the trial. Twenty three healthy controls were enrolled for T cell subsets detection at the same time with the trial. The t-stochastic neighbor embedding (tSNE) analysis of CD4 T subsets based on immune cells flow cytometry markers was performed to distinguish Tfh, Tfh1, Tfh2, Tfh17 and Tfr cell subsets. Results: Compared with HC, the frequency of Tfr (CXCR5+PD-1lowTreg and CXCR5+PD-1highTreg) cells was significantly reduced, while the pro-inflammatory Tfh cells were increased in patients with SLE. The imbalanced Tfh cell was associated with several pathogenic factors (anti-dsDNA antibodies (r=0.309, P=0.027) and serum IL-17 (r=0.328, P=0.021)) and SLE Disease Activity Index (SLEDAI) score (r=0.273, P=0.052). Decreased CXCR5+PD-1lowTreg/Tfh and CXCR5+PD-1lowTreg/Tfh17 were both associated with increased immunoglobulin M (IgM) (r=-0.448, P=0.002 and r=-0.336, P=0.024 respectively). Efficacy of low-dose IL-2 therapy was associated with a restored Tfr/Tfh cell balance.Conclusion: These data supports the hypothesis that promotion of Tfr associated with decreased disease activities, and that low-dose IL-2 therapy can recover Tfr/Tfh immune balance.Trial registration number ClinicalTrials.gov Registries (NCT02465580).