title: Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis.
abstract: OBJECTIVE
  Premature 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.
  
  
  METHODS
  Eighty-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.
  
  
  RESULTS
  In 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 generatedin vitroby 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.
  
  
  CONCLUSIONS
  In 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.
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz , Graz , Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Fessler
authors.affiliation: Department of Pediatric Hemato-Oncology, Medical University of Graz , Graz , Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raicht
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz , Graz , Austria.
authors.forename: Rusmir
authors.initials: R
authors.lastname: Husic
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz , Graz , Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Ficjan
authors.affiliation: Department of Pediatric Hemato-Oncology, Medical University of Graz , Graz , Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Schwarz
authors.affiliation: Department of Internal Medicine VI, Innsbruck Medical University , Innsbruck , Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Duftner
authors.affiliation: Department of Pediatric Hemato-Oncology, Medical University of Graz , Graz , Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schwinger
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz , Graz , Austria.
authors.forename: Winfried B
authors.initials: WB
authors.lastname: Graninger
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz , Graz , Austria.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Stradner
authors.affiliation: Department of Rheumatology and Immunology, Medical University of Graz, Graz, Austria; Rheumatology Service, South Tyrolian Health Trust, Hospital Bruneck, Bruneck, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Dejaco
keywords: aging; autoimmunity; immunosenescence; premature; regulatory T cells; rheumatoid arthritis