Control of mucosal immunity and intestinal integrity by human gamma/delta T cells

Human 'unconventional' lymphocytes are increasingly recognised to sense pathogens, influence recruitment and function of other immune cells, and help protect body tissues against infection. This project will study how gamma delta T cells in human blood and intestine control 'conventional' CD4+ T cell responses in health and disease. Polarisation of CD4+ T helper cells into Th1, Th2, Th17 and Treg 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 help 5 / 18 inform the development of novel vaccines, treatments and diagnostics for a range of pathologies.

Our data demonstrate a striking plasticity of human gamma delta T cells to modulate immunity at epithelial sites. A previous PhD student already identified gamma delta T cell signals that drive expression of the tissue-protective factors IL-22 and calprotectin in the human intestine. More recent work shows that human gamma delta T cells can also induce anti-inflammatory CD4+ T cell responses marked by the expression of IL-10.

To define the molecular mechanisms underlying CD4+ T cell polarisation by human gamma delta T cells during homeostasis and infection, and to identify ways to manipulate relevant pathways for future interventions

- To study the potential of human gamma delta T cells to polarise primary CD4+ T cells towards distinct T helper subsets
- To define the molecular signals that polarise CD4+ T cells towards distinct effector subsets by RNAseq profiling of activated human gamma delta T cells.
- To validate polarising signals and manipulate pathways in cell culture, human intestinal tissues and gut-on-a-chip systems.
- To investigate polarising pathways in mouse models: in vitro/in vivo T cell polarisation by signals identified in Aims 2+3 (with focus on CD4+ T-cells producing IL-10 or IL-22, and signalling via ICOS/ICOSL and CD30/CD30L).