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Title: The roles of CD40 and OX40 during the induction of T cell tolerance versus T cell immunity
Author: Hochweller, Kristin
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Tolerance induction is thought to be the result of peptide presentation by resting DC, which are lacking full costimulatory potential. The precise signals that drive a T cell towards tolerance, rather than a productive immune response, are not well defined. This project has addressed this issue by asking three questions: A. Can exogenous ligation of defined costimulatory receptors convert a tolerogenic signal into an immunogenic one? B. How does expression of the costimulatory pairs CD40-CD154, OX40L-OX40, and RANK-RANKL on DC or T cells respectively differ during induction of T cell tolerance versus immunity? C. Can we mimic tolerance induction by giving antigen-loaded DC lacking CD40? It was found that agonistic antibodies to CD40 and OX40 converted a tolerance signal to an immunogenic one, preventing the induction of tolerance. CD154, OX40 and RANKL are expressed on T cells under conditions leading to either tolerance or immunity. Up-regulation/induction of CD40, OX40L and RANK on DC, however, was only observed during the induction of T cell immunity. The administration of antigen-loaded CD40-deficient DC mimicked tolerance induced by soluble peptide. Collectively, the results suggest that the CD40-CD154 interaction provides an important checkpoint in the decision between T cell tolerance and immunity. Investigating the process of tolerance induction may provide a rational basis for therapeutic targeting of costimulatory pairs in adverse immune reactions in humans.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available