Investigating immune recognition of an epithelial stress antigen by Human gamma delta T cells AND Investigation into the chemokine profile of Ag-specific T cell responses in Multiple Myeloma and MGUS patients compared to age-matched controls.

摘要

Project 1: The ‘lymphoid stress surveillance’ hypothesis proposes a role for γδ T cells in in the detection of epithelial stress. TCR mediated recognition of stress ligands by γδ T cells is currently poorly understood. This project aimed to characterise the molecular mechanisms of the interaction between of the Vδ1+ MAU γδ TCR with the ephrin receptor EphA2. EphA2 is a major target for anti-cancer treatments, and is upregulated on a range of epithelial tumours, a tissue enriched with Vδ1+ γδ T cells. We show that EphA2 activates MAU expressing JRT3.5 cells in a TCR dependant manner, by receptor downregulation and phosphorylation of key TCR proximal signalling proteins. It was also found that A-ephrins on the surface of the T cell are essential for the activation of JRT3 MAU by EphA2.ududProject 2: Multiple Myeloma (MM) is an incurable haemopoietic malignancy, characterised by the accumulation of malignant plasma cells in the Bone Marrow (BM). MM cells express a group of proteins called Cancer Testis Antigens (CTA) whose expression is limited to the immune-privileged site of the testis in healthy adults. CTA specific CD8+ T cells in MM patients display poor in vivo effectiveness, and are poorly understood. Immuno dysregulation is a common occurrence in MM, with a dysregulation in the distribution and expression of key chemokines involved in lymphocyte trafficking such as CXCR3 and CXCR4, which may be a defensive mechanism by the tumour to protect against CTA specific T cells. This project aimed to characterise the chemokine receptor expression on CTA specific CD8+ T cells in MM patients, and it was discovered that MM patients have a reduction in CXCR3 and CXCR4 expression on CD8+ T cells in the blood, and that the chemokine receptor expression pattern of different viral specific CD8+ T cells are affected uniquely by MM.ud