Award Title: Elucidating functional and spatial characteristics of CD8+ T cell populations in coeliac disease
Funder: The Academy of Medical Sciences

Abstract: Celiac disease (CD) is common, increasing in prevalence, and leads to significant morbidity and impaired quality of life for patients. Treatment with a gluten-free diet is burdensome, and there is a significant unmet need for improved diagnostics and therapeutics. Whilst the role of the gluten-specific CD4+ T cell in CD immunopathology is well-studied, the cytotoxic CD8+ T cell populations are less well understood. Specifically, the role of TCR-dependent CD8+ T cell processes in CD, and the antigens that drive them, remain unknown.

Our recent work has identified a population of intestinal CD8+ T cells, restricted by a particular TRB V gene (TRBV28), which are highly enriched in both active and treated CD. This population displays features of shared antigen-restriction and clonal expansion, with an activated, cytotoxic, high-regulated phenotype. We hypothesize that this novel CD8 population has an unappreciated role in CD pathogenesis, potentially responding to as yet uncharacterised key antigens.

This work seeks to explore the functions, cell-cell interactions, and spatial localisation of this CD8+ T cell population. Specifically I will:
1. Define the transcriptional and phenotypic responses of intestinal TRBV28+ CD8+ T cells in CD to cytokine and TCR stimulation using combined single-cell gene expression/protein assays. 
2. Examine the localisation and potential cell-cell interactions of intestinal TRBV28+ CD8+ T cells in CD using spatial transcriptomic approaches. 
3. Test putative cell-cell interaction pathways in vitro intestinal-derived T cell clones.

This work may provide insights into our understanding of CD pathogenesis, with potential translational benefits including novel diagnostic and therapeutic strategies.

Lay Abstract: In coeliac disease (CD), gluten in the diet triggers the immune system to damage the gut lining, leading to troublesome abdominal symptoms. Treatment with a gluten-free diet is challenging and impairs quality of life. There is a real unmet need for better CD tests and treatments.

In CD, one immune cell subtype, CD4+ (helper) T-cells, respond directly to gluten and trigger the inflammation. However, we know less about T-cells in the gut lining (epithelium), the CD8+ (killer) T-cells. These cells directly cause gut damage in CD. We do not fully understand what activates them and how they cause damage.

Our previous work found one type of CD8+ T-cell (identified by a surface receptor) is highly enriched in CD. This persists even with treatment. These cells look like they are responding to a specific, unknown signal (antigen), and may be causing inflammation. This project will examine what this interesting cell population does when stimulated, where they are in the gut, and what other cells they interact with.

We will study their role using methods which explore the genes activated in individual cells (single-cell RNAseq) and how this changes with stimulation. We will then map the location and gene expression of these cells in the gut. This will help us understand what these cells do in CD, where they are acting, and with which other cells they are interacting.

In summary, this project will explore the role of this new cell type in CD, which may lead to improved tests and treatments.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: ORAL AND GASTROINTESTINAL