Abstract
ObjectiveTo 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.MethodsA 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.ResultsCompared 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.ConclusionThese 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 numberClinicalTrials.gov Registries (NCT02465580).
Highlights
Systemic lupus erythematosus (SLE) is characterized by the breakdown of immune tolerance leading to autoreactive immune responses and tissue and organ damages
Characteristics of SLE patients Given recent studies showing the imbalances in the effector and regulatory T follicular helper cells (Tfh) cell compartment in SLE patients [3, 4], and in light of our finding that low-dose IL2 treatment significantly influences Tfh subtypes, we recruited a small cohort of healthy controls (HC) (n=23, Table 1) for comparative analysis
There was no significant difference between patients and HCs regarding age or gender. 98% of the SLE patients were positive in antidsDNA tests, 42% had renal involvement, and 48% had skin manifestations
Summary
Systemic lupus erythematosus (SLE) is characterized by the breakdown of immune tolerance leading to autoreactive immune responses and tissue and organ damages. Extensive studies on regulatory T (Treg) cells have revealed that these cells can maintain tolerance and regulate immune responses [1, 2], while T follicular helper cells (Tfh) play an important role in the production of autoantibodies and pro-inflammatory cytokines in SLE [3,4,5]. Imbalance or disfunction of Tfr subsets may directly or indirectly affect B cells, leading to expansion of overactive B cells which contributes to various immune-related clinical diseases [14, 15]. The role of balance between Tfh and Tfr subsets in SLE is still controversial due to the heterogeneity of the disease, cohort size, and methods of studies [16, 17]
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