Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis

Abstract

BackgroundRegulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4+CD25−LAG3+ T cells (LAG3+ Tregs) and their association with rheumatoid arthritis (RA).MethodsLAG3+ Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3+ Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4+ T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays.ResultsLAG3+ Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25+ Tregs. Cell-to-cell contact was required for the suppressive function of LAG3+ Tregs. The frequency of LAG3+ Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3+ Tregs significantly increased after 6 months of abatacept treatment, whereas CD25+ Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4+ T cells, and abatacept-treated CD4+ T cells exhibited suppressive activity.ConclusionsIL-10-producing LAG3+ Tregs are associated with the immunopathology and therapeutic response in RA. LAG3+ Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1309-x) contains supplementary material, which is available to authorized users.

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

“…Response to treatment with tocilizumab, an IL-6 receptor inhibitor, is associated with higher baseline frequencies of natural killer (CD3 − CD56 + ) cells [80] and higher increases in the frequencies of T REG cells in the periphery [81]. A case-control study of RA patients and healthy controls demonstrated that IL-10+ producing LAG3 + T REG cells are specifically increased after treatment with abatacept, and that the magnitude of this increase is correlated with the strength of response [82]. Immunoprofiling studies have also revealed changes in the function of lymphocyte populations in response to therapy: for example, RA patients who respond well to anti-TNF treatment have higher production of GM-CSF from T cells [83].…”

Alopecia areata patients show deficiency of FOXP3+CD39+ T regulatory cells and clonotypic restriction of Treg TCR?-chain, which highlights the immunopathological aspect of the disease

“…These findings are supported by LAG-3 expression, which showed no difference between the groups ( Figure 1B). The activation gene (LAG3) has been reported as a marker of IL-10 producing Treg [27]. Taking these findings together suggests that impaired Treg function in AA is mainly due to a defect in cell-to-cell contact and CD39-mediated suppressive machinery and not in cytokine secretion.…”

CD4+CD25−LAG3+ regulatory T cells in humoral immunity

“…Similar to murine LAG3 + Tregs, these human LAG3 + T cells produce large amounts of IL‐10 in response to TCR stimulation and suppress humoral immunity. When the frequency of LAG3 + Tregs in the peripheral blood of rheumatoid arthritis patients was examined, it was lower in patients with rheumatoid arthritis, especially those with higher disease activity . Further studies are required to evaluate the role of human LAG3 + Tregs in other autoimmune diseases.…”