Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis

Abstract

ObjectivePremature senescence of lymphocytes is a hallmark of inflammatory rheumatic diseases such as rheumatoid arthritis (RA). Early T-cell aging affects conventional T-cells but is presumably not limited to this cell population; rather it might also occur in the regulatory T-cells (Tregs) compartment. In RA, Tregs fail to halt aberrant immune reactions and disease progression. Whether this is associated with early Treg senescence leading to phenotypic and functional changes of this subset is elusive so far.MethodsEighty-four RA patients and 75 healthy controls were prospectively enrolled into the study. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed for phenotypic and functional analyses of Treg subsets. T-cell receptor excision circle (TREC) levels and telomere lengths were determined using RT-PCR.ResultsIn this paper, we describe the novel CD4+FoxP3+CD28− T-cell subset (CD28− Treg-like cells) in RA patients revealing features of both Tregs and senescent T-cells: Treg surface/intracellular markers such as CD25, CTLA-4, and PD-1 as well as FOXP3 were all expressed by CD28− Treg-like cells, and they yielded signs of premature senescence including reduced TREC levels and an accumulation of γH2AX. CD28− Treg-like could be generated in vitro by stimulation of (CD28+) Tregs with TNF-α. CD28− Treg-like cells insufficiently suppressed the proliferation of effector T-cells and yielded a pro-inflammatory cytokine profile.ConclusionIn conclusion, we describe a novel T-cell subset with features of Tregs and senescent non-Tregs. These cells may be linked to an aberrant balance between regulatory and effector functions in RA.

Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression

“…It has been proposed that acquisition of a cytotoxic phenotype in senescent T cells may be compensatory for losses observed in T and NK cells [27]. Moreover, a recent study proposed the existence of a subset of senescent Treg cells in the peripheral environment of RA [28]. These cells were defined as CD4 + CD28-Foxp3+ T cells and were positively associated with age and with clinical parameters such as disease activity and treatment.…”

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

“…Similarly, immunoprofiling of T REG cells in RA described the discovery of a novel senescent-like T REG cell population characterized by the loss of CD28 expression and increased numbers of double stranded DNA breaks. Compared to standard T REG cells, CD28 − T REG cells had impaired suppressive function and produced higher amounts of proinflammatory cytokines IFN-γ and TNF [76•]. …”

Circulating Exosomal miR-17 Inhibits the Induction of Regulatory T Cells via Suppressing TGFBR II Expression in Rheumatoid Arthritis

“…We and other groups have shown that a reduction of Treg frequency is an immunological hallmark of RA [3,4,17]. Because exosomes were shown to contribute to intercellular communication by transporting signals into the target cells either close to or distant from the cells of exosome origin [12,16], we investigated the effect of RA-exosomes on Treg differentiation and found that RA-exosomes could inhibit Treg differentiation in vitro.…”