- Title
- Characterisation of CD4+ T-helper 22 lymphocytes during bacterial infection of the mucosa
- Creator
- Barnes, Jessica Lee
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2023
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- CD4+ T helper lymphocytes (Th cells), comprise several functionally distinct subsets, which are central to host-defence against specific pathogens at cutaneous and mucosal barriers. However, dysregulation of Th cell mediated immunity leads to deleterious inflammation and barrier dysfunction that underpins a range of chronic inflammatory diseases (CID). The specific pathophysiological processes that underlie intractable CID are complex and not fully understood. Moreover, the inherent diversity of CD4+ T cells and their role in host defence complicates effective treatment. There is a need to delineate the molecules that specify discrete Th cell subset identities, to inform unique druggable targets to modulate their function in disease. Th22 cells are recognised as a phenotypically distinct Th cell subset that feature high IL-22 production, however the in-depth characterisation if this cell has been incomplete. As a consequence, the distinct molecular mechanisms by which Th22 cells elicit protective versus pathogenic functions, independent of other defined lineages such as Th17 cells, are not known. The manuscript presented in Chapter 2 established, through IL-17A fate-mapping, that a distinct subset of Th22 cells arises as a lineage separate from the Th17 cell effector program within infected mucosal tissues and their draining lymph nodes following bacterial infection of the lung and gut – although in some compartments alternative transition pathways were identified. The master transcriptional regulator T-bet was identified as a T-cell-intrinsic suppressor of Th17 and Th22 -cell development, and cytokine secretion, during respiratory bacterial infection. T-bet played essential but divergent roles in mediating signature gene expression, phenotypic stability, and bi-directional plasticity in these two Th subsets. The study presented in Chapter 3 employed newly generated cytokine-reporter transgenic mice to delineate the transcriptional identity of Th22 cells isolated from infected mucosa. This analysis disclosed a divergent transcriptional profile for Th22 cells from defined IL-17A and IFNγ-producing Th cell subsets, a cross-species pan-tissue conserved core gene-set, and selective expression of a stem-cell like gene signature suggestive of multipotent progenitor potential. The work presented in this thesis has significantly improved our understanding of endogenous Th22 cell development, identity, heterogeneity and potential for phenotypic flexibility during mucosal anti-bacterial immune responses.
- Subject
- CD4 T-cell; adaptive immunity; Th22; Th17; bacterial infection; Citrobacter rodentium; Chalmydia muridarum; IL-22
- Identifier
- http://hdl.handle.net/1959.13/1471404
- Identifier
- uon:48669
- Rights
- This thesis is currently under embagro and will be available from 15.02.2025., Copyright 2023 Jessica Lee Barnes
- Language
- eng
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