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Title: Regulation of lymphocyte trafficking to the human gut in physiology and disease
Author: Wang, Amu
ISNI:       0000 0004 2711 928X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Memory T cell recruitment to the non-lymphoid tissue of the intestine (the gut lamina propria) requires the interactions between integrin a4B7 and its ligand Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), which is exclusively expressed in the gut microvasculature. T cell homing to small intestine also requires the expression of chemokine receptor CCR9 on T cells, whose ligand - the gut chemokine CCL25 - is abundantly expressed in the small intestine. The a4B7 integrin and chemokine receptor CCR9 are known as the "homing" molecules whose expression is "imprinted" on T cells by intestinal dendritic cells during antigen presentation. In the first part of this thesis, data from in vitro studies showed that other than retinoic acid, soluble tissue-derived factors such as the gut chemokine CCL25 and T cell growth factor IL-2 also contributed to the induction of gut-homing receptor acquisition. Moreover, the expression of a4B7 integrin and CCR9 appeared to be modulated differently. The present study suggests that under the influence of tissue-derived factors, T cell acquisition of a4B7 integrin is the "default" response at steady state, and that only fully activated T cells are able to express high levels of CCR9. In the second part of this thesis, T cell gut homing was investigated in the context of disease, i.e. inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). IBD is characterized by excessive lymphocyte infiltration to the intestine. By quantitatively analyzing peripheral blood and intestinal lymphocyte subsets, proportional changes in the circulating gut-homing T cells (a4B7+) was found to be associated with CD. In addition, my data suggest that downregulation of T cell receptor zeta chain (TcRC) correlates to disease severity in both CD and UC. Measuring TcRC expression may thus provide an additional tool for the monitoring and management of IBD.
Supervisor: Marelli-Berg, Federica ; Orchard, Timothy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral