Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-beta1 on CD4+ and CD8+ naïve human T-cells

2.50
Hdl Handle:
http://hdl.handle.net/2336/56398
Title:
Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-beta1 on CD4+ and CD8+ naïve human T-cells
Authors:
Gunnlaugsdottir, Brynja; Maggadottir, Solrun M; Ludviksson, Björn R
Citation:
Int. Immunol. 2005, 17(1):35-44
Issue Date:
1-Jan-2005
Abstract:
TGF-beta1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-beta1 is affected by its phenotype or signaling intensity. In the present study, we demonstrate that the phenotype and the TCR-signaling intensity of the responding T-cell as well as the presence of anti-CD28 co-stimulation markedly affects how naïve human cord blood T-cells respond to TGF-beta1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-beta1. Thus, the greatest anti-proliferative effect of TGF-beta1 was observed during weak stimulatory conditions (low dose of anti-CD3 with no co-stimulatory signal). However, such anti-proliferative effect was reduced during strong stimulatory signal (high dose of anti-CD3 with a CD28-directed co-stimulatory signal). In addition, our results indicate that CD8+ T-cells are generally more responsive towards TGF-beta1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFNgamma and TNFalpha, but low amounts of IL-4, IL-5 and IL-10. TGFbeta1 significantly reduced the secretion of IL-2 and IFNgamma, but such suppression was partially prevented by anti-CD28-induced co-stimulation. In contrast, the inhibitory effect on IL-5 secretion was unaffected by anti-CD28 co-stimulation. Interestingly, TGF-beta1 induced IL-10 and TNFalpha secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-beta1 further induced TNFalpha secretion. These data demonstrate that the duration, intensity and type of signaling alters the sensitivity of T-cells to powerful immunological modifying agents like TGF-beta1.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://intimm.oxfordjournals.org/cgi/content/abstract/17/1/35

Full metadata record

DC FieldValue Language
dc.contributor.authorGunnlaugsdottir, Brynja-
dc.contributor.authorMaggadottir, Solrun M-
dc.contributor.authorLudviksson, Björn R-
dc.date.accessioned2009-03-19T11:28:54Z-
dc.date.available2009-03-19T11:28:54Z-
dc.date.issued2005-01-01-
dc.date.submitted2000-03-19-
dc.identifier.citationInt. Immunol. 2005, 17(1):35-44en
dc.identifier.issn0953-8178-
dc.identifier.pmid15557315-
dc.identifier.doi10.1093/intimm/dxh183-
dc.identifier.urihttp://hdl.handle.net/2336/56398-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractTGF-beta1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-beta1 is affected by its phenotype or signaling intensity. In the present study, we demonstrate that the phenotype and the TCR-signaling intensity of the responding T-cell as well as the presence of anti-CD28 co-stimulation markedly affects how naïve human cord blood T-cells respond to TGF-beta1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-beta1. Thus, the greatest anti-proliferative effect of TGF-beta1 was observed during weak stimulatory conditions (low dose of anti-CD3 with no co-stimulatory signal). However, such anti-proliferative effect was reduced during strong stimulatory signal (high dose of anti-CD3 with a CD28-directed co-stimulatory signal). In addition, our results indicate that CD8+ T-cells are generally more responsive towards TGF-beta1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFNgamma and TNFalpha, but low amounts of IL-4, IL-5 and IL-10. TGFbeta1 significantly reduced the secretion of IL-2 and IFNgamma, but such suppression was partially prevented by anti-CD28-induced co-stimulation. In contrast, the inhibitory effect on IL-5 secretion was unaffected by anti-CD28 co-stimulation. Interestingly, TGF-beta1 induced IL-10 and TNFalpha secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-beta1 further induced TNFalpha secretion. These data demonstrate that the duration, intensity and type of signaling alters the sensitivity of T-cells to powerful immunological modifying agents like TGF-beta1.en
dc.language.isoenen
dc.publisherOxford University Pressen
dc.relation.urlhttp://intimm.oxfordjournals.org/cgi/content/abstract/17/1/35en
dc.subject.meshAntigens, CD28en
dc.subject.meshAntigens, CD3en
dc.subject.meshCD4-Positive T-Lymphocytesen
dc.subject.meshCD8-Positive T-Lymphocytesen
dc.subject.meshCell Survivalen
dc.subject.meshCytokinesen
dc.subject.meshHumansen
dc.subject.meshLymphocyte Activationen
dc.subject.meshNecrosisen
dc.subject.meshReceptors, Antigen, T-Cellen
dc.subject.meshTransforming Growth Factor betaen
dc.subject.meshTransforming Growth Factor beta1en
dc.titleAnti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-beta1 on CD4+ and CD8+ naïve human T-cellsen
dc.typeArticleen
dc.contributor.departmentCenter for Rheumatology Research, Landspitali-University Hospital, Reykjavik, Iceland.en
dc.identifier.journalInternational immunologyen
All Items in Hirsla are protected by copyright, with all rights reserved, unless otherwise indicated.