Characterisation of the immunomodulatory properties of human natural killer T cells
Hogan, Andrew E. (2010) Characterisation of the immunomodulatory properties of human natural killer T cells. PhD thesis, National University of Ireland Maynooth.
Invariant natural killer (iNKT) cells are a small subset of innate cells which express an invariant T cell receptor and NK surface molecules and recognize glycolipid antigen presented by CD1. iNKT cells have shown potent anti-tumour properties when stimulated with the iNKT cell agonist α-galactosylceramide (αGalCer) in murine models. However iNKT cell based immunotherapies have proved disappointing in phase I and II clinical trials to date. Humans have a wider repertoire of CD1-restricted T cells compared to mice. These CD1 restricted T cells are poorly defined in healthy human blood. In this study we investigated the reactivity of CD1 in human blood, we identified in healthy donors the majority of CD1 reactive T cells were identified as iNKT cells. We optimized a method to readily isolate and expand iNKT from human peripheral blood. iNKT stimulated with synthetic analogues of αGalCer have shown the potential as tailored adjuvants for dendritic cell (DC) based immunotherapy. We established a system to test the immunostimulatory ability of iNKT cell analogues on DC maturation and function. A novel αGalCer analogue α-S-GalCer stimulated iNKT cell line to produce a Th1 biased cytokine response and lyse tumour cells. α-SGalCer stimulated iNKT cells also induced maturation of monocyte derived DC, and stimulated DC to produce Th1 biased cytokines. Furthermore DC matured by α-S-GalCer stimulated iNKT cells proliferated allogeneic T cell and induced Th1 cytokine production by the same. This data shows that the novel iNKT agonist α-S-GalCer stimulates iNKT cell lines in a Th1 biased fashion and induces DC maturation. Results suggests that α-SGalCer may possibly be an attractive adjuvant for iNKT/DC based cell immunotherapy for malignancies and viruses.
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