Defining MR1-ligand expression in human and mouse tissues
Lead supervisor: Prof. Paul Klenerman
Co-supervisor: Prof. Benjamin Fairfax
Commercial partner: Immunocore
MR1 (MHC Related Molecule 1) is an important immunologic molecule that presents ligands to unconventional T cells. These ligands are non-peptide small molecules of two types. The first are derived from microbes that can synthesize riboflavin. The classic ligand in this class is 5-OP-RU, which is recognised by an abundant T cell subset described as Mucosal Associated Invariant T cells (MAIT), in a manner that is conserved between mouse and human. Where MAIT cells contact MR1 presenting this ligand in vivo under steady-state conditions and in disease is not known. This is of significance in infection and also in cancer, where MAIT cells appear to play a role in the response to checkpoint inhibitor therapy. In a collaboration between Immunocore and Oxford we are currently exploring the use of a MAIT TCR molecule with optimised affinity to define the distribution of MR1-ligand. With such a reagent we aim to define the functional partners of MAIT cells in healthy and diseased tissue, in human and in mouse.
The second type of ligand has only recently been described and is derived from “self” rather than microbes. A prototype of such a ligand is a nucleobase, with carbonyl adducts – potentially derived as a result of cellular stress. This type of ligand is recognised by MR1-T cells which are distinct from MAITs on the basis of their T cell receptors and phenotype. Much less is known about the functions of these MR1-T cells and they are poorly described in mice. In this project we also aim to make similar studies of MR1-T receptor binding, ligand distribution and potential association with disease states. A previous MRC iCase student with Immunocore generated many relevant tools and a database of TCRs, so with the additional data on ligand type we hope to make rapid progress.
In this project we aim to:
1. Define the TCR usage and critical immuno-phenotypic features of MR1-T cells in health and disease
Our data from a prior project indicate some shared TCR usage amongst MR1-T cells. We will first extend this experimental database using an unbiased screen and also a ligand-based screen to identify critical determinants of MR1-T interaction with MR1. We will explore the phenotype and function of such MR1-T cells using scRNAseq based methods from patient samples including healthy tissue, inflammation, cancer and infection. We will perform similar experiments in mice to test if the same biology is shared across species (as it is for MAIT cells).
2. Create a new soluble TCR library based on MR1-T TCRs.
We will identify MR1-restricted TCRs and generate a new set of soluble molecules with high specificity and sensitivity based on the TCR biology pipelines at Immunocore. We will explore both a ligand-based and an unbiased approach. We will define the functionality of such TCRs in health and disease and test their capacity to stain MR1 positive cells. Specifically we will explore the hypothesis that cellular stress drives presentation of MR1-T ligands.
Apply using course: DPhil in Clinical Medicine
