International Immunology Advance Access published online on November 22, 2004
International Immunology, doi:10.1093/intimm/dxh183
© 2004 by The Japanese Society for Immunology
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1 Center for Rheumatology Research, Department of Immunology, Landspitali-University Hospital, Reykjavik, Iceland; Institute for Medical Laboratory Sciences, Department of Immunology, Landspitali-University Hospital, Reykjavik, Iceland
* To whom correspondence should be addressed. TGF-
Accepted October 8, 2004
Article
Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-
1 on CD4+ and CD8+ naïve human T-cells
2 Center for Rheumatology Research, Department of Immunology, Landspitali-University Hospital, Reykjavik, Iceland; Institute for Medical Laboratory Sciences, Department of Immunology, Landspitali-University Hospital, Reykjavik, Iceland; Department of Medicine, National University of Iceland, Reykjavik, Iceland
Björn R. Ludviksson, E-mail: bjornlud{at}landspitali.is
Abstract 
1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-1 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-1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-1. Thus, the greatest anti-proliferative effect of TGF-1 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-1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFN
and TNF
, but low amounts of IL-4, IL-5 and IL-10. TGF1 significantly reduced the secretion of IL-2 and IFN, 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-1 induced IL-10 and TNF secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-1 further induced TNF 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-1.1; T Lymphocytes; cellular proliferation; costimulation; anergy.
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