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.
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
Project reference number: 979
|Professor Paul Klenerman||Experimental Medicine Division||Oxford University, Peter Medawar Building||GBRemail@example.com|
|Dr Carolina Arancibia||Experimental Medicine Division||Oxford University, John Radcliffe Hospital||GBRfirstname.lastname@example.org|
|Dr Chris Willberg||Experimental Medicine Division||Oxford University, Peter Medawar Building||GBRemail@example.com|
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