| Description: |
Coeliac disease (CD) is caused by an adaptive immune response to gluten, however the gluten- specific CD4+ T cell response is insufficient to cause tissue damage in isolation. CD8+ intra-epithelial T cells (IELs) mediate epithelial cell damage in CD, which is thought to occur in a TCR-independent manner, while the role of γδ IELs, which are increased in CD, remains enigmatic. I sought to investigate CD8+ and γδ T cell populations in CD. After optimisation of intestinal tissue dissociation, TCR repertoire sequencing (TCRseq) and single- cell RNA sequencing (scRNAseq) (Chapter 3), I examined intestinal CD8+ and γδ T cells in CD using flow cytometry, bulk and single-cell RNAseq, and TCRseq (Chapter 4). I confirmed previously reported changes in γδ TCR repertoires in CD, and identified perturbations in the CD8+ TCR repertoire, including enrichment of TRBV28-expressing clonotypes in CD. Bulk and scRNAseq approaches identified an activated, cytotoxic, highly regulated, tissue-resident population of CD8+ T cells associated with CD, which were associated with these TRBV28 clonotypes, consistent with a TCR-driven CD8+ T cell process involved in CD pathogenesis. This work on CD led further research in two directions, examining the wider landscape of human γδ T cells and their relationships to other innate-like T cells, and exploring CD8+ T cell heterogeneity in tissue resident populations in the human gut. First, I examined transcriptional, phenotypic, and functional heterogeneity in human γδ T cells (Chapter 5). scRNAseq and flow cytometry of circulating γδ T cells revealed a Vδ2+ γδ T cell effector spectrum, from an innate-like, cytokine-responsive CD26bright population to a highly cytotoxic GPR56+ population. CD26bright Vδ2+ T cells were highly similar to MAIT cells, in transcriptional profile, phenotype, and function, in particular in their IFNγ- and IL-26-dominated response to cytokine stimulation. In addition, unexpected heterogeneity within naive non-Vδ2 T cell populations was identified, including a SOX4+ subset ... |