Determining important novel mechanisms that regulate T-cell-mediated immune responses

Abstract

The immune system protects our body against foreign pathogens, being capable of promptly mounting a response against different insults. Nevertheless, immunity must be tightly regulated to prevent aberrant responses targeted against our tissues. TGF-beta is a pleiotropic cytokine regulating immune responses, which the active cytokine moiety is non-covalently bound to the latency associated peptide (LAP). The activation state of latent TGF-beta is regulated by the integrin alpha(v)beta(8) - which engages with LAP to promote cytokine activation. On dendritic cells (DC), integrin alpha(v)beta(8)-mediated TGF-beta activation is paramount - as conditional loss of this integrin correlates with severe inflammatory bowel disease in mice. Additionally, current studies in our lab indicate that expression of alpha(v)beta(8) is high in effector memory T cells (Tem), with unpublished work indicating that alpha(v)beta(8)+ Tem suppress anti-viral immunity in mice. Importantly, members of the integrin family can act as signalling receptors, but pathways regulated by alpha(v)beta(8) upon ligand engagement have not been well described to date, with no information available for how integrin alpha(v)beta(8) signals in immune cells. In this PhD thesis, we used a transcriptomic approach with the aim of identifying important signalling pathways regulated by integrin alpha(v)beta(8) in DC and T cells. Specifically, using RNA-seq analysis we found that expression of CXCR4 was downregulated in LAP-treated DC and that correlated with a reduced migrating behaviour toward the CXCR4-specific chemokine, CXCL12. These data might indicate that prior to TGF-beta activation, signals propagated in DC limit their migrating behaviour. Also, transcriptome profiling indicates that alpha(v)beta(8)+ Tem marked a transcriptionally distinct cell population from the alpha(v)beta(8)- counterparts and are significantly enriched with anti-inflammatory pathways. These data complement previous findings in our lab, providing insights into why a newly identified subset of CD4+ memory T cells can inhibit anti-viral responses. Together, these results indicate previously undetermined pathways that are regulated by alpha(v)beta(8) in DC and T cell biology.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Mark Travis (Supervisor) & Jean-Marc Schwartz (Supervisor)