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Title: The influence of IL-10 on dendritic cell activation
Author: Perona-Wright, Georgia
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Dendritic cells (DCs) are the watchmen of the immune system. They survey the peripheral tissues and display samples of surrounding antigens for inspection by T cells. Pathogenic or inflammatory signals trigger DCs to mature, upregulating their expression of MHC and costimulatory molecules and converting them into potent T cell stimulators. The character of the activated DC depends not only on the stimulus but also on concomitant environmental signals. This thesis tests the hypothesis that in vitro manipulation of DC function can be used to direct immune responses in vivo. The work focuses on the cytokine IL-10 and asks whether its impact on DC maturation can mediate T cell tolerance. IL-10 has been reported to trap DCs in an immature state, leading to antigen presentation without full costimulation and consequent T cell anergy. Data presented here show that DCs do become activated in the presence of IL-10. They downregulate antigen uptake and, 6 hours after stimulation, display high levels of MHCII and B7. Their activation is short-lived, with both MHC and B7 expression returning to baseline within 18h. Even at 6 hours, with high levels of surface MHC and costimulation, the IL-10 treated DCs express little 1L-12 and fail to elicit strong T cell proliferation. IL-10 seems not to act by inhibiting DC maturation but instead by dictating the kinetics and quality of their activation. The consequence of this DC activation for the responding T cells is also examined. Both in vitro and in vivo, using co-cultures and adoptive transfers of TCR transgenic T cells followed by DC-based immunisation, initial contact with IL-10 treated DCs appears to leave T cells hyporesponsive to subsequent challenge. In a mouse model of autoimmunity, these DCs suppress disease. Taken together these data suggest that, rather than preventing DC maturation, IL-10 directs an active DC phenotype that can regulate immune responses. These DCs have exciting therapeutic potential.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available