title: CD4(+) CD25(low) GITR(+) cells: a novel human CD4(+) T-cell population with regulatory activity.
abstract: Treg subsets play a role in sustaining peripheral tolerance, are characterized by markers such as forkhead winged-helix transcription factor (FOXP3) and CD25, and produce suppressive cytokines, such as IL-10 and TGF-β. Glucocorticoid-induced TNF receptor family-related (GITR) protein has been suggested to regulate Treg activity in mice. The aim of our study was to investigate GITR expression in human CD4(+) T lymphocytes and its possible role in Treg function. Results indicate that a subset of CD4(+) T cells in the peripheral blood expresses GITR and low levels of CD25 (CD4(+) CD25(low) GITR(+) ). These cells show Treg features as they express FOXP3, IL-10, TGF-β and are anergic but, as opposed to natural Tregs, express low levels of CTLA-4 and are CD127(high) . CD4(+) CD25(low) GITR(+) cells represent a low percentage of the CD4(+) T-cell population (0.32-1.74%) and are mostly memory cells. Functional experiments demonstrated that CD4(+) CD25(low) GITR(+) cells have relevant suppressive activity that depends on TGF-β. Moreover, an anti-GITR Ab inhibited their suppressive activity, as observed in CD4(+) CD25(+) murine Tregs. Taken together, these data indicate that human CD4(+) CD25(low) GITR(+) cells represent a distinct Treg subpopulation.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy. rodolfo.bianchini@sbg.ac.at
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bianchini
authors.forename: Onelia
authors.initials: O
authors.lastname: Bistoni
authors.forename: Alessia
authors.initials: A
authors.lastname: Alunno
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Petrillo
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.forename: Elena Bartoloni
authors.initials: EB
authors.lastname: Bocci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Roberto
authors.initials: R
authors.lastname: Gerli
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D005434:Flow Cytometry; D015870:Gene Expression; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C491405:TNFRSF18 protein, human; D016212:Transforming Growth Factor beta; D016753:Interleukin-10