title: Characterization of a new regulatory CD4+ T cell subset in primary Sjögren's syndrome.
abstract: OBJECTIVE
  CD4(+)CD25(low)GITR(+) T lymphocytes expressing FoxP3 and showing regulatory function have been recently described in healthy donors (HD). The objective of the study was to investigate their presence and role in patients with primary SS (pSS).
  
  
  METHODS
  CD4(+)CD25(low)GITR(+) cells circulating in peripheral blood (PB) of patients with pSS were isolated by MACS technique, their phenotype was studied by flow cytometry and real-time PCR, and their function was studied by in vitro co-culture. CD4(+)CD25(low)GITR(+) cells infiltrating salivary glands (SGs) were revealed by immunohistochemistry.
  
  
  RESULTS
  Results indicated that conventional CD4(+)CD25(high) regulatory T cells (Tregs) are decreased, whereas CD4(+)CD25(low)GITR(+) cells are expanded in the PB of pSS as compared with HD. Phenotypic analysis demonstrated that CD4(+)CD25(low)GITR(+) cells display Treg markers, including FoxP3, TGF-β and IL-10, and functional experiments demonstrated that they exert a strong inhibitory activity against autologous effector cells. CD4(+)CD25(low)GITR(+) cells were detectable in great number in the SG inflammatory infiltrate. Interestingly, PB CD4(+)CD25(low)GITR(+) cell expansion was evident only in patients with inactive disease, while conventional CD4(+)CD25(high) Treg number was not associated with disease activity.
  
  
  CONCLUSIONS
  The present data demonstrate that circulating CD4(+) cells expressing GITR, but with low levels of CD25 (CD4(+)CD25(low)GITR(+)), are detectable in pSS patients. These cells, displaying Treg phenotype and function, are present in SG inflamed tissues and are expanded in the PB of subjects with inactive disease. Data suggest that the expansion of CD4(+)CD25(low)GITR(+) cells in pSS may represent a counter-regulatory attempt against autoimmune-driven inflammation and may provide a new target for future treatment strategies.
authors.affiliation: Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Perugia, Via Enrico Dal Pozzo, I-06122 Perugia, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Alunno
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Petrillo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Onelia
authors.initials: O
authors.lastname: Bistoni
authors.forename: Elena
authors.initials: E
authors.lastname: Bartoloni
authors.forename: Sara
authors.initials: S
authors.lastname: Caterbi
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bianchini
authors.forename: Chiara
authors.initials: C
authors.lastname: Baldini
authors.forename: Ildo
authors.initials: I
authors.lastname: Nicoletti
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Gerli
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D018709:Statistics, Nonparametric; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
keywords: GITR; Sjögren’s syndrome; regulatory T cells