The TIGER project

Project Overview

TIGER (T cells - Innate-like, Gut-Enriched and Resident) is a project to discover new innate-like T cells in the human gut. We originally identified CD161+ T cell populations in the liver (eg MAIT cells and Vd2 cells) which have an overlapping set of properties - commensal reactive, innate-like (responding to IL12 and 18) and enriched in tissue. These have a combination of a distinct phenotype and a distinct specificity, associated with a distinct TCR usage. Such cells are involved in normal host defence and possess a range of properties which include tissue repair as well as host defence, including against viruses. Given the abundance of these populations in humans, we believe there are more cell types out there to be discovered which could be important in health and disease.

In TIGER we will follow up on new populations of T cells from the human gut and demonstrate that they are

1. Commensal specific

2. Define the restricting allele(s) which may include novel molecules.

3. Define the ligand.

We will address to what extent these cells are involved in disease by examining samples from patients with inflammatory bowel disease, celiac disease and liver inflammation.

Training Opportunities

T cell immunology, FACS, FACS sorting, single cell genomics, CRISPR screens and functional screens will be used to hone in on the populations of interest. This will include T cell cloning, associated with sequencing, transfection and generation of reagents to address the specificity of particular populations

Theme

Immunology & Infectious Disease and Genetics & Genomics

Admissions

Project reference number: 979

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Paul Klenerman Experimental Medicine Division Oxford University, Peter Medawar Building GBR paul.klenerman@medawar.ox.ac.uk
Dr Carolina Arancibia Experimental Medicine Division Oxford University, John Radcliffe Hospital GBR carolina.arancibia@ndm.ox.ac.uk
Dr Chris Willberg Experimental Medicine Division Oxford University, Peter Medawar Building GBR chris.willberg@ndm.ox.ac.uk

van Wilgenburg B, Scherwitzl I, Hutchinson EC, Leng T, Kurioka A, Kulicke C, de Lara C, Cole S, Vasanawathana S, Limpitikul W, Malasit P, Young D, Denney L, STOP-HCV consortium, Moore MD, Fabris P, Giordani MT, Oo YH, Laidlaw SM, Dustin LB, Ho LP, Thompson FM, Ramamurthy N, Mongkolsapaya J, Willberg CB, Screaton GR, Klenerman P. 2016. MAIT cells are activated during human viral infections. Nat Commun, 7 pp. 11653. Read abstract | Read more

Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology. Hide abstract