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Title: Immune modulation using inducible lineage-specific transcription factors
Author: Andersen, K. G.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2009
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The launch of an immune response is regulated on several different levels. Whilst responses against foreign antigens proceed relatively unrestricted, CD4+CD25+ regulatory T cells suppress potential immune attacks directed against self. During their development in the thymus these cells start to express the lineage-specific transcription factor Foxp3, which is both required and sufficient for their development and function. I have identified functional domains of Foxp3 that were differentially required for its function as a master regulator of gene expression. I extended these studies by generating a series of reporter constructs, which were used to measure some of the cellular consequences of Foxp3 expression in vivo and in vitro. I have also showed that ectopic expression of Foxp3 in CD4+CD25- T cells leads to a significant downregulation of the homing factor CD62L. This appeared to result in these cells being excluded from the peripheral lymph nodes, with a subsequent failure to expand ‘appropriately’ upon immunological challenge. By utilising a genetically engineered inducible version of Foxp3 (iFoxp3), I circumvented these problems and showed that cells expressing iFoxp3 both homed ‘correctly’ into lymph nodes and partook in immune responses. In two different animal models of autoimmune disease, I showed that T cells transduced with iFoxp3, but not Foxp3, could be used to control and treat such disorders. Finally, I went on to show that the iFoxp3-mediated suppression was specific to the antigen(s) the cells partook in prior to the induction of iFoxp3.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available