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

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 the standard of care treatment. The primary endpoint was the attainment of SLE responder index-4 (SRI-4) at week 12 in the trial. Twenty-three healthy controls were enrolled for T cell subset detection at the same time as 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-1low Treg and CXCR5+PD-1high Treg) 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-1low Treg/Tfh and CXCR5+PD-1low Treg/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 support the hypothesis that promotion of Tfr is 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).

Efficacy and Safety of Low-Dose Interleukin 2 for Primary Sjögren Syndrome

“… 35 We have previously demonstrated that IL-2 therapy inhibits Tfh differentiation and promotes Treg cells and T follicular regulatory subset, which resulted in reduced autoantibody production and decreased immune complex levels. 36 , 37 This might alleviate the activation of pDCs or monocytes to lower IFN-α levels.…”

Altered Circulating Follicular T Helper Cell Subsets and Follicular T Regulatory Cells Are Indicators of a Derailed B Cell Response in Lupus, Which Could Be Modified by Targeting IL-21R

“…A balanced IL-2/CD25 signaling is critical for maintaining not just T FR but also T FH generation, because IL-2 could suppress both cells; nevertheless, it is required for Treg development. Two studies demonstrated that a carefully adjusted, prolonged low-dose IL-2 treatment led to the recovery of T FR /T FH immune balance and successfully mitigated pathogenic B cell responses, as well as kidney damage [ 50 , 51 ]. All these results support the use of T FR cells as an attractive therapeutic target in lupus.…”

Progress and prospects of biologics and small molecules for the treatment of patients with systemic lupus erythematosus

“…A randomized, double-blind, and placebocontrolled clinical trial of low-dose interleukin-2 (IL-2) in treatment of SLE showed that low-dose IL-2 may sustain cellular immunity with enhanced natural killer cells, as well as expansion of regulatory T cells [33]. Low-dose IL-2 therapy can recover T follicular regulatory (Tfr) and T follicular (Tfh) immune balance [34]. A good response was achieved in patients with lower regulatory T cells (Treg) proportion and skin rash in SLE patients with low-dose IL-2 treatment [35].…”