Investigating the immuno-regulatory roles of beta2 integrins

McIntyre, Claire Lindsay (2019) Investigating the immuno-regulatory roles of beta2 integrins. PhD thesis, University of Glasgow.

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Abstract

The balance of the immune system between activation versus tolerance is essential for mounting responses to pathogens whilst preventing excessive or inappropriate responses that cause host damage. The β2 integrins (CD11a/b/c/d) are leukocyte-specific adhesion receptors that play essential roles in regulating immune responses. Many studies have focussed on the roles of β2 integrins in contributing to immune activation including: leukocyte migration, immune synapse formation and phagocytosis. However, there is evidence that β2 integrins can also play immuno-regulatory roles. The overall aim of this thesis was to explore the regulatory roles of β2 integrins in dendritic cells (DCs) and γδ T cells.

Previous studies have shown in the absence of functional β2 integrins, DCs display enhanced activation and are capable of inducing greater T cell responses. I identified that specifically, the absence of CD11a or CD11c, but not CD11b or CD11d, leads to increased co-stimulatory molecule expression on DCs generated in vitro and greater numbers of DCs in the spleen in vivo. CD11a knockout (KO) DCs were also capable of inducing enhanced T cell responses. These findings are the first to highlight CD11a and CD11c as negative regulators of DC function.

In studies using β2 integrin-deficient mice, the development of skin and oral mucosal inflammation are associated with an expansion of γδ T cells therefore, I hypothesised that β2 integrins are a novel regulator of γδ T cells. I characterised γδ T cells in β2 integrin (CD18) KO mice and found an increased number of Vγ6Vδ1+ γδ T cells in the spleen, blood, lungs and uterus with enhanced IL-17 production. Thymic development of Vγ6+ cells was unaffected by integrin loss but development of Vγ4+ cells was impaired. Vγ6+ cells showed similar proliferative capacity however, this subset was associated with reduced expression of apoptotic markers, indicating the accumulation of these cells is likely due to increased survival. Together, this data highlights a previously undescribed role for β2 integrins in promoting Vγ4+ γδ T cell development and regulating Vγ6+ γδ T cell numbers in the periphery.

These findings emphasise the importance of β2 integrins in regulating immune responses. Further work to understand the downstream pathways of this regulation will identify potential therapeutic targets for diseases where DC or γδ T cell responses are dysregulated.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: beta2 integrin, dendritic cell, γδ T cell.
Subjects: Q Science > QR Microbiology > QR180 Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Supervisor's Name: Morrison, Dr. Vicky
Date of Award: 2019
Depositing User: Ms Claire McIntyre
Unique ID: glathesis:2019-71941
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 15 May 2019 10:47
Last Modified: 15 May 2019 10:50
URI: http://theses.gla.ac.uk/id/eprint/71941

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