The Wilms tumour antigen is a promising target for T cell-based tumour immunotherapies. Vaccines against WT1 peptides tested in cancer patients showed immunological and molecular responses. However, the clinical responses observed were partial and it is currently not known whether physiological levels of WT1 expression in some healthy tissues results in the deletion or tolerance induction of WT1-specific T cells. In this PhD project, TCR gene transfer into purified haematopoietic stem cells (HSCs) was used to study the thymic development of WT1-specific T cells and their fate in the periphery. Lentiviral constructs containing the genes for an HLAA2 allorestricted, murinised WT1 TCR or the genes for a control, viral peptide-specific, LMP2 TCR, were generated. The conditions for lentivirally-transduced HSC transplants were optimised. The results obtained from WT1 TCR tranduced HSC transplants in HLA-A2Kb transgenic mice demonstrated that thymocytes expressing this high-avidity WT1 TCR were positively selected into CD8 T cells and emerged in the recipient’s periphery. WT1-specific T cells exhibited a memory, CD44hi phenotype correlating with rapid antigen specific killing, proliferation and cytokine secretion of WT1-specific T cells in the absence of vaccination. LMP2-specific T cells exhibited a naive-like, CD44low phenotype without any antigen specific function. WT1-specific T cells persistent long-term in the periphery of transplanted mice, and no autoimmunity was noted. The results presented in this thesis show for the first time that T cell specificity for a tumour-associated, self-antigen did not result in tolerance induction, but instead mediated the spontaneous generation of functionally competent, memory phenotype T cells.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:568290 |
| Date | January 2012 |
| Creators | Pospori, C. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1369532/ |
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