Control of adaptive immunity in health and inflammation by human blood and mucosal gamma/delta T cells
Application deadline: 23 November 2018
Start date: October 2019
Research theme: Infection, immunity and repair
So-called 'unconventional' lymphocytes sense pathogens, regulate recruitment and function of other immune cells, and help protect the skin and intestine. This project will study how microbe-responsive γδ T-cells in human blood and intestine control 'conventional' CD4+ T-cell responses in health and inflammation. Polarisation of CD4+ T helper cells is crucial for host defence against pathogens and tumours, but also for wound healing and resolution of inflammation. Better understanding of this process will therefore inform the development of novel vaccines, treatments and diagnostics for a range of human pathologies.
Our recent data demonstrate a striking plasticity of γδ T-cells to modulate immunity at epithelial sites and during infection. A previous PhD student identified γδ T-cell signals that drive expression of the tissue-protective factors IL-22 and calprotectin in the intestine. Unpublished work shows that γδ T-cells can also induce regulatory and anti-inflammatory CD4+ T-cell responses.
Aims and method
The objective of this project is to define the molecular mechanisms underlying CD4+ T-cell polarisation by γδ T-cells and identify ways to manipulate them for future interventions. You will work across disciplinary boundaries, by combining functional studies using murine and human cells, bioinformatics approaches, analyses of human intestinal biopsies, and in vivo models of inflammation.
- To study the potential of human γδ T-cells to polarise primary CD4+ T-cells towards distinct T helper subsets (Th1, Th2, Th9, Th17, Th22, Tr1, Tfh, Treg) as characterised by cytokine and transcription factor profiles.
- To identify polarising signals by gene expression profiling (RNAseq) of activated γδ T-cell populations that polarise CD4+ T-cells towards distinct effector subsets.
- To validate polarising signals in cell culture and human tissues, by studying expression of corresponding molecules in blood and intestine, and using agonists/antagonists to manipulate pathways in γδ:CD4+ T-cell co-cultures.
- To validate polarising pathways in mouse models: in vitro/in vivo T-cell polarisation by signals identified in Aim 2; relevance in murine CMV infection (focus on CD4+ T-cells producing IL-10 or IL-22).
Techniques include flow cytometry, cell sorting, immunohistochemistry, confocal microscopy, ELISA, qPCR, RNAseq, Ingenuity Pathway Analysis and infection studies in mice.
This project will benefit from established local collaborations with Nick Kent (RNAseq) and Rob Andrews (bioinformatics). In addition to publications and presentations at scientific meetings, specialist and lay audiences will be reached via the group's websites and social media, Cardiff University, the British Society for Immunology, the γδ T-cell Forum and via the engagement and involvement activities of the Systems Immunity URI in Cardiff and the Centre of the Cell in London.
Dr Neil McCarthy, Queen Mary University of London.