Regulatory T cells shape the CD4 T cell response to Salmonella

Clay, Slater Lowe (2019) Regulatory T cells shape the CD4 T cell response to Salmonella. PhD thesis, University of Glasgow.

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Abstract

FoxP3+ regulatory T cells (Tregs) play an important role in controlling inflammation and maintaining homeostasis at mucosal sites. Tregs may also limit immunopathology during infection but their role in this context remains poorly understood. CD4 T helper (Th) cells are important drivers of immune responses and can express master transcription factors (TFs) including T-bet, GATA3 and RORγT, which identify Th1, Th2 and Th17 cells, respectively. Tregs can also express these TFs, and recent research suggests that Tregs expressing master TFs may be able to selectively suppress their corresponding Th subsets. T-bet+ Tregs have been shown to selectively target Th1 cells in some contexts, but it is unclear whether the same dynamic occurs with Tregs expressing other TFs. It is also unclear whether selective suppression can influence the overall CD4 T cell bias during infection. To address these questions, an infection model using Salmonella enterica serotype Typhimurium (STM) was developed to induce non-lethal colitis. This allowed STM-specific and polyclonal CD4 T cells to be tracked in multiple tissues.

Using this model, a dynamic and site-specific CD4 T cell response was revealed. An early and transient colonic Th17 response was followed by a sustained Th1 bias. This Th response develops in parallel with an early increase in the proportion of T-bet+ Tregs and a later increase in the proportion of RORγT+ Tregs. This reciprocal dynamic between Th subsets and Tregs expressing the same TF is consistent with the hypothesis that specific populations of Tregs selectively suppress Th subsets. To determine if Tregs are required for the dynamic Th bias, Treg depletion experiments were carried out at different timepoints. Results show that Tregs are essential for both the early Th17 response and the later Th1 response. Together, these results support the hypothesis that Tregs shape the dynamic Th bias by selective suppression. Further research is needed to address what mechanism might drive this targeted regulation. This research shows the potential for Tregs to not just inhibit the overall T cell response, but to actively shape Th bias. This highlights the potential for Tregs expressing specific TFs to be used in targeted therapeutic approaches. Further work is warranted to improve our basic understanding of how Tregs shape immunity and to develop appropriate clinical applications.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Grant no.: MRC/1654776.
Keywords: CD4 T cells, regulatory T cells, Tregs, Salmonella, mucosal immunology, colitis, infection, inflammation, immune regulation, intestine, colon.
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: Milling, Professor Simon W.F.
Date of Award: 2019
Depositing User: Slater Clay
Unique ID: glathesis:2019-72998
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 10:28
Last Modified: 11 Jun 2019 10:31
URI: http://theses.gla.ac.uk/id/eprint/72998

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