Type I diabetes (T1D) is an autoimmune disease in which the insulin producing β cells of the pancreas are selectively targeted for destruction by autoimmune effector T cells. The aberrant effects of these effector T cells may in part be due to a dysfunction in the regulatory T cell (TREG) compartment and currently there is great interest in developing methods to strengthen the immunoregulation of patients with T1D. A potential way to boost immunoregulation in these patients would be the use of adoptive TREG therapy whereby expanded polyclonal TREG are transferred into patients. Although this treatment in mouse models of disease has shown promise it has been found that antigen specific TREG cells are much more efficacious of preventing disease, and can even reverse disease. The translation of these murine experiments into the human setting is however complex, since the generation of large numbers of antigen specific TREG from human patients is currently a major hurdle. One way to remove this barrier is to utilise lentiviral gene transfer technology, which can allow for the transfer of antigen specific T cell receptor (TCR) genes into a desired cell population. Specifically for T1D, it is hypothesised that TREG engineered to express a MHC Class I restricted (MHCI) TCR, although unconventional, would selectively function at the site of inflammation i.e. within the islets. This project, therefore, aims to generate MHCI islet antigen specific TREG with the hypothesis that these would confer islet antigen specific suppression. To test this hypothesis we engineered human CD4+ TREG to express two MHCI islet antigen specific TCRs whilst using a third high affinity pathogenic MHCI TCR as a control. As others have shown, we demonstrate that the control TCR was effectively able to re-direct the antigen specificity of TREG cells through signalling and function. However, we discovered that transfer of autoimmune MHCI TCRs were unable to yield the same results as the control TCR due in part to their natural low affinity for antigen. To circumvent this, we engineered CD4+ TREG to express an MHCI autoimmune TCR along with the CD8αβ co-receptor or a CD8αβ high affinity variant. Using this system, human TREG could be successfully re-directed towards an islet specific peptide and exhibit antigen specific suppression. Thus, this study is the first of its kind to use an autoimmune disease relevant, MHCI TCR to successfully re-direct the Ag specificity of TREG cells.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677123 |
| Date | January 2015 |
| Creators | Nickolay, Lauren Emma |
| Contributors | Peakman, Mark ; Tree, Timothy Ian Martin |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://kclpure.kcl.ac.uk/portal/en/theses/the-generation-of-mhc-class-i-restricted-islet-antigen-specific-regulatory-t-cells-for-the-treatment-of-type-1-diabetes(394a4c36-5f32-47b4-ba22-aa10463160e6).html |
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