CD3+CD4+gp130+ T Cells Are Associated With Worse Disease Activity in Systemic Lupus Erythematosus Patients.

Nur Diyana Mohd Shukri,Aziz Farah Izati,Che Maraina Che Hussin,Kah Keng Wong,Wan Syamimee Wan Ghazali

doi:10.3389/fimmu.2021.675250

Nur Diyana Mohd Shukri, Aziz Farah Izati + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2021.675250

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Abstract

The receptors for IL-35, IL-12Rβ2 and gp130, have been implicated in the inflammatory pathophysiology of autoimmune diseases. In this study, we set out to investigate the serum IL-35 levels and the surface levels of IL-12Rβ2 and gp130 in CD3+CD4+, CD3+CD4─ and CD3─CD4─ lymphocyte subpopulations in systemic lupus erythematosus (SLE) patients (n=50) versus healthy controls (n=50). The potential T cell subsets associated with gp130 transcript (i.e. IL6ST) expression in CD4+ T cells of SLE patients was also examined in publicly-available gene expression profiling (GEP) datasets. Here, we report that serum IL-35 levels were significantly higher in SLE patients than healthy controls (p=0.038) but it was not associated with SLEDAI-2K scores. The proportions of IL-12Rβ2+ and gp130+ cells in SLE patients did not differ significantly with those of healthy controls in all lymphocyte subpopulations investigated. Essentially, higher SLEDAI-2K scores were positively correlated with increased proportion of gp130+ cells, but not IL-12Rβ2+ cells, on CD3+CD4+ T cells (r=0.425, p=0.002, q=0.016). Gene Set Enrichment Analysis (GSEA) of a GEP dataset of CD4+ T cells isolated from SLE patients (n=8; GSE4588) showed that IL6ST expression was positively associated with genes upregulated in CD4+ T cells vs myeloid or B cells (q<0.001). In an independent GEP dataset of CD4+ T cells isolated from SLE patients (n=9; GSE1057), IL6ST expression was induced upon anti-CD3 stimulation, and that Treg, TCM and CCR7+ T cells gene sets were significantly enriched (q<0.05) by genes highly correlated with IL6ST expression (n=92 genes; r>0.75 with IL6ST expression) upon anti-CD3 stimulation in these SLE patients. In conclusion, gp130 signaling in CD3+CD4+ T cell subsets may contribute to increased disease activity in SLE patients, and it represents a promising therapeutic target for inhibition in the disease.

Highlights

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by loss of immune tolerance, production of autoantibodies, imbalanced cytokine levels and their downstream signaling pathways [1, 2]
We set out to determine the levels of serum IL-35 and surface levels of IL-12Rb2 and gp130 in lymphocyte subpopulations i.e. CD3+CD4+, CD3+CD4─ and CD3─CD4─ cells of SLE patients compared with healthy controls
Serum IL-35 was elevated in SLE patients compared with healthy controls with borderline significance (p=0.038) (Figure 2A)

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by loss of immune tolerance, production of autoantibodies, imbalanced cytokine levels and their downstream signaling pathways [1, 2]. IL-35 is a novel cytokine in the IL-12 family produced by regulatory T cells (Tregs), regulatory B cells (Bregs), activated dendritic cells and monocytes [9,10,11,12]. It is similar with other IL12 family of cytokines which function as heterodimers where each cytokine comprises of heterodimeric subunits (an asubunit and a b-subunit). IL-35 exerts pro-inflammatory effects by activating the production of IL-12 and IFN-g [15], and its expression is upregulated in autoimmune diseases such as rheumatoid arthritis (RA) where it augments the release of pro-inflammatory factors such as IL-1b and IL-6 [16]. In SLE, multiple studies have reported that serum IL-35 levels are increased in established SLE patients on treatment [17, 18]

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