Flash Talk & Poster CD1-MR1 2024

Characterisation of MR1-reactive T cell responses using newly developed MR1-ligand tetramers (#137) (#20)

Michael Souter 1 , Wael Awad 2 3 , Clarice Lee 1 , Lucy Meehan 1 , Yang Kang 1 , Songyi Li 1 , Adam Nelson 1 , Lyudmila Kostenko 1 , Bronwyn Meehan 1 , Chu-Han Huang 1 , Ching-Seng Ang 4 , Jeffrey Mak 5 , Thanh Nguyen 6 , Thi HO Nguyen 1 , Katherine Kedzierska 1 , Spencer Williams 6 , David Fairlie 5 , Sidonia Eckle 1 , Alexandra Corbett 1 , Jamie Rossjohn 2 3 7 , Lars Kjer-Nielsen 1 , Zhenjun Chen 1 , James McCluskey 1
  1. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  2. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  3. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
  4. Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Parkville, Victoria, Australia
  5. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  6. School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
  7. Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff, United Kingdom

MR1 is a major histocompatibility complex (MHC) class I-like molecule that presents microbial metabolites derived from the riboflavin biosynthesis pathway to mucosal-associated invariant T (MAIT) cells. Numerous studies now report that MR1 can bind a plethora of other small molecules of microbial, environmental, synthetic, or endogenous cellular origin, some of which may be recognised by MAIT cells or other MR1-reactive T cells in the context of infection, allergy, autoimmunity, or cancer. Many of these known or proposed MR1 ligands exist as structurally related families of chemical adducts with highly reactive cellular dicarbonyls such as glyoxal, methylglyoxal, and malondialdehyde (MDA). Using a selection of newly described MR1 ligands of such nature, we generated MR1 tetramers to identify and extensively characterise MAIT and other MR1-reactive T cell responses in the blood from healthy human donors.

 

We found that adducts of MDA were presented by MR1 and recognised by two distinct populations of T cells: namely, MAIT cells bearing unique T cell receptors (TCRs) and non-MAIT, predominantly CD8+, T cells bearing diverse TCRs. These MR1-reactive T cells were present at a low frequency in blood but were detected in almost all healthy donors after enrichment. MAIT and non-MAIT MR1-reactive T cells exhibited varying degrees of antigen-dependent as well as allomorph-dependent MR1 reactivity and produced T helper (Th)1 type cytokines upon stimulation. Polyclonal MR1-reactive T cells from healthy donors displayed potent cytotoxicity to transformed and tumour-derived cell lines. Our findings demonstrate that MR1-reactive T cells are common in healthy donors and that these cells bear TCRs with the collective capacity to recognise and elicit immunity to MR1 furnishing structurally distinct molecules from a burgeoning diversity of sources.