Tumour associated antigens (TAAs) are up-regulated on malignant cells but may be expressed on normal tissues. Transfer of highly-avid cytotoxic T cells specific for TAAs may either cause auto-immune damage to normal tissues or transferred cells may lose efficacy through deletion or development of tolerance. CD8+ T cells recognising a Major Histocompatibility Complex class 1 (MHC-I) restricted epitope of the Murine Double Minute (MDM2) TAA were generated by T cell receptor (TCR) gene transduction. I then designed a model of tolerance in which MDM2 specific CD8+ T cells were transferred into lymphodepleted antigen-bearing hosts. These cells persisted but showed defective specific in vivo cytotoxicity where antigen was ubiquitous, or confined to non-haematopoietic tissues. In antigen-free hosts they remained efficient killers. Provision of CD4 help by OT-II T cells led to increased frequency and cytotoxicity of MDM2-specific CD8+ T cells. I then tested whether MDM2 TCR-transduced CD4+ cells could act as a helper population. Co-transfer of MDM2 TCR-transduced CD4+ and CD8+ cells improved antigen-specific killing of the CD8+ T cells. This was not due to specific killing activity of the MDM2 specific CD4+ T cells, and was not provided by a mock-transduced CD4+ population. Thus, transduction with an MHC-I restricted TCR generated TAA specific CD8+ T cells which became dysfunctional on antigen exposure, but could also generate a helper population capable of rescuing them from tolerance in vivo. Since the MDM2 TCR is CD8 dependent, CD4 T cells bearing this TCR have a lower avidity than their CD8+ counterparts. They therefore fell below the activation threshold for development of tolerance in antigen-bearing hosts, and could act as helpers in vivo. This strategy may be a novel approach to overcoming CD8+ T cell tolerance to TAAs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626642 |
| Date | January 2014 |
| Creators | Ghorashian, S. |
| 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/1420999/ |
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