title: T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells.
abstract: CD4(+)CD25(+) regulatory T (T reg) cells play a pivotal role in control of the immune response. Transforming growth factor-beta (TGF-beta) has been shown to be required for T reg cell activity; however, precisely how it is involved in the mechanism of suppression is poorly understood. Using the T cell transfer model of colitis, we show here that CD4(+)CD45RB(high) T cells that express a dominant negative TGF-beta receptor type II (dnTbetaRII) and therefore cannot respond to TGF-beta, escape control by T reg cells in vivo. CD4(+)CD25(+) T reg cells from the thymus of dnTbetaRII mice retain the ability to inhibit colitis, suggesting that T cell responsiveness to TGF-beta is not required for the development or peripheral function of thymic-derived T reg cells. In contrast, T reg cell activity among the peripheral dnTbetaRII CD4(+)CD25(+) population is masked by the presence of colitogenic effector cells that cannot be suppressed. Finally, we show that CD4(+)CD25(+) T reg cells develop normally in the absence of TGF-beta1 and retain the ability to suppress colitis in vivo. Importantly, the function of TGF-beta1(-/-) T reg cells was abrogated by anti-TGF-beta monoclonal antibody, indicating that functional TGF-beta can be provided by a non-T reg cell source.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Fahlén
authors.forename: Simon
authors.initials: S
authors.lastname: Read
authors.forename: Leonid
authors.initials: L
authors.lastname: Gorelik
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hurst
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D016207:Cytokines; D015375:Receptors, Interleukin-2; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1