Dysregulated ICOS+ proinflammatory and suppressive regulatory T cells�in patients with rheumatoid arthritis

Abstract

Regulatory T cells (Tregs) serve an important role in the pathogenesis of rheumatoid arthritis (RA) by regulating autoimmunity and inflammation. Humans and mice contain inducible T-cell costimulator-positive (ICOS) Tregs, although their role in RA is unclear. A total of 33 patients with RA and 17 normal control (NC) subjects were examined. The proportion of ICOS Tregs in the peripheral blood and intracellular cytokine levels in these cells were assessed using flow cytometry. The percentage of ICOS Tregs increased in the cohort of patients with RA compared with the NCs. Such increases were much larger in patients with inactive RA compared with patients with active RA. Additionally, ICOS Tregs expressed multiple suppressive cytokines, including interleukin (IL)-10, transforming growth factor-β and IL-35, but expressed low levels of IL-17. Importantly, the expression of suppressive cytokines in ICOS Tregs from patients with active RA decreased, but IL-17 expression noticeably increased compared with patients with inactive RA. The present findings suggested that ICOS Tregs may perform inflammatory and inhibitory functions, and abnormal ICOS Tregs numbers and functions may contribute to the pathogenesis of RA.

Regulatory T cells in psoriatic arthritis: an IL-17A-producing, Foxp3intCD161 + RORγt + ICOS + phenotype, that associates with the presence of ADAMTSL5 autoantibodies

“…To our knowledge, this is the first study to perform in-depth phenotypical characterization of Tregs derived from the inflammatory microenvironment of inflamed joints in patients with psoriatic disease. Here, we provide evidence for Treg variance in PsA by showing distinct phenotypical and functional properties of intra-articular Tregs as compared to Tregs in circulation: downregulation of key transcription factor Foxp3, increased cytokine production, upregulation of inhibitory immune receptors, and upregulation of markers that have been reported to associate with a pro-inflammatory potential of Tregs: CD161, RORγt and ICOS 7,14,15,30,31,[37][38][39] .…”

“…4A and B). Moreover, we included ICOS in our phenotypical Treg characterization, because ICOS + Tregs can play a proinflammatory, pathogenic role in inflammatory arthritis and immune diseases 31,32 . We observed a comparable expression pattern as for the inhibitory receptors: synovial fluid derived Tregs express more ICOS, as compared to Tregs in circulation (Fig.…”

“…However, studies in the last decade have suggested a possible role for ICOS + Tregs in pathogenesis, contributing to autoimmune rheumatic disease. In lupus, RA and spondyloarthritis, associations were found of ICOS expression by Tregs with high disease activity, with non-response to therapy, increased autoantibodies, and pro-inflammatory cytokine production 31,[37][38][39] . Since we show that all intra-articular Tregs upregulate ICOS expression, even independent of Foxp3 expression, further investigation is warranted for ICOS + Tregs as possible therapeutic target for treatment of psoriatic disease.…”

“…For the standard curve, we used 50 µL primary anti-human-ADAMTSL5 antibodies in duplo (HPA044050-100UL, Sigma-Aldrich), serially diluted in 2% BSA in PBS in the following concentrations: 5.00, 1.67, 0.56, 0.1852, 0.0617, 0.0206, 0.0069 μg/mL. After overnight incubation at 4°C, we incubated patient sample wells with 50 µL/well horseradisch-peroxidase (HRP)-conjugated anti-human IgG (11,869,130,ThermoFisher Scientific) and standard curve wells with 50 µL HRP-conjugated anti-rabbit IgG (31,460,Thermofisher). We developed and stopped the color reaction with 50 µL/well of 3,3′, 5,5′-tetramethylbenzidine (TMBW-1000-01, Tebu-Bio) and 2 N H 2 SO 4 , respectively.…”

In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways

“…Whereas in RA patients, ICOS+ Tregs were increased compared to normal controls, and such an increase was accentuated in patients with inactive RA compared to patients with active RA. Additionally for the patients with active RA the expression of suppressive cytokines (IL-10, TGF-β and IL-35) decreased while, expression of IL-17 increased compared with inactive RA, suggesting that ICOS+ Tregs may play an inflammatory and inhibitory function in a context-dependent manner ( 77 ).…”