Popple, Amy Lee (2012) The tumour microenvironment influences antigen specific T cell transmigration. PhD thesis, University of Nottingham.
T cell infiltration into tumours is essential for tumour antigen recognition and tumour cell elimination. The aim of this study was to develop a better understanding of T cell infiltration into tumours, focusing on two opposing arms of an immune response, anti-tumour CD8 Tcells and Regulatory T cells (Tregs). Activated CD4 T helper cells are also of importance but could not be studied due to the time constraints of the project. The effect of T cell signalling at the immunological synapse following interactions between T cells and APCs presenting cognate antigen have been well studied . The endothelium is neither a stereotypical APC nor simply a passive filter barrier for non-cognate infiltrating T cells. The endothelium can activel influence the development of an inflammatory response depending on the functional state of both the endothelium and interacting T cells (resting versus recently activated T cells)and the type of interactions (cognate versus non-cognate). The hypothesis was that recognition of antigens presented in the context of major histocompatibility complex (MHC)molecules by endothelium aids T cell transmigration and hence infiltration into tissues, including into tumours.
In this study, the data highlights that high avidity TRP-2 specific CD8 T cell transmigration across murine lung endothelium requires recognition of TRP-2 peptide presented by the endothelium, aiding recruitment of antigen-specific T cells into tissues in the absence of endothelial cell killing. In order for antigen specific T cells to migrate into the tumour, the tumour endothelium therefore needs to present tumour antigens.
In addition to CD8 T cells, high numbers of Tregs have been found within tumours but the key mediators for this recruitment remain uncertain. The data shows a novel mechanism for Treg transmigration where cognate antigen-specific recognition of self-peptides was required for transmigration with preferential transmigration of Tregs across syngeneic rather than allogeneic endothelium. Upregulation of major histocompatibility complex (MHC) class II and adhesion molecules, by IFN-γ and TNF-α, together with a gradient of the tumour associated chemokine CXCL12 were also pre-requisites for efficient Treg transmigration.Previous studies have shown that high CXCL12 expression can induce fugetaxis of tumour cells leading to efficient metastatic spread and a poor prognosis. These results would suggest that low levels of CXCL12 and recognition of self peptides presented by self MHC on endothelial cells allows efficient migration of Tregs whereas higher levels of CXCL12 may promote tumour metastases and lead to fugetaxis of the Tregs leading to an even worse prognosis.
In conclusion recognition of cognate antigen presented by endothelium enhances antigenspecific transmigration of CD8 and Regulatory T cells. This study therefore reports a novel mechanism for T cell subset infiltration into tumours where high avidity CD8 T cells require recognition of cognate tumour antigen presented on tumour endothelium in the context of MHC class I and conversely regulatory T cell infiltration into tumours depends on the repertoire of self-peptides presented on tumour endothelium in the context of MHC class II. Alteration of antigen presentation or MHC expression on tumour endothelium therefore represents a mechanism whereby T cell infiltration can be altered to re-direct anti-tumour immune responses.
|Item Type:||Thesis (PhD)|
|Faculties/Schools:||UK Campuses > Faculty of Medicine and Health Sciences > School of Molecular Medical Sciences|
|Deposited By:||Miss A.L. Popple|
|Deposited On:||10 Oct 2012 11:41|
|Last Modified:||10 Oct 2012 11:41|
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