title: Expansion of regulatory GITR+CD25 low/-CD4+ T cells in systemic lupus erythematosus patients.
abstract: BACKGROUND
  CD4+CD25 low/-GITR+ T lymphocytes expressing forkhead box protein P3 (FoxP3) and showing regulatory activity have been recently described in healthy donors. The objective of the study was to evaluate the proportion of CD4+CD25 low/-GITR+ T lymphocytes within CD4+ T cells and compare their phenotypic and functional profile with that of CD4+CD25 high GITR- T lymphocytes in systemic lupus erythematosus (SLE) patients.
  
  
  METHODS
  The percentage of CD4+CD25 low/-GITR+ cells circulating in the peripheral blood (PB) of 32 patients with SLE and 25 healthy controls was evaluated with flow cytometry. CD4+CD25 low/-GITR+ cells were isolated with magnetic separation, and their phenotype was compared with that of CD4+CD25 high GITR- cells. Regulatory activity of both cell subsets was tested in autologous and heterologous co-cultures after purification through a negative sorting strategy.
  
  
  RESULTS
  Results indicated that CD4+CD25 low/-GITR+ cells are expanded in the PB of 50% of SLE patients. Expansion was observed only in patients with inactive disease. Phenotypic analysis demonstrated that CD4+CD25 low/-GITR+ cells display regulatory T-cell (Treg) markers, including FoxP3, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), transforming growth factor-beta (TGF-β), and interleukin (IL)-10. In contrast, CD4+CD25 high GITR- cells appear to be activated and express low levels of Treg markers. Functional experiments demonstrated that CD4+CD25 low/-GITR+ cells exert a higher inhibitory activity against both autologous and heterologous cells as compared with CD4+CD25 high GITR- cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-β.
  
  
  CONCLUSIONS
  Phenotypic and functional data demonstrate that in SLE patients, CD4+CD25 low/-GITR+ cells are fully active Treg cells, possibly representing peripheral Treg (pTreg) that are expanded in patients with inactive disease. These data may suggest a key role of this T-cell subset in the modulation of the abnormal immune response in SLE. Strategies aimed at expanding this Treg subset for therapeutic purpose deserve to be investigated.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Alessia
authors.initials: A
authors.lastname: Alunno
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Petrillo
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: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Gerli
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C491405:TNFRSF18 protein, human