Poster Presentation CD1-MR1 Workshop 2025

Allelic variation of MR1 shapes its antigen repertoire and presentation capacity (#116)

Adam G Nelson 1 , Victoria Letoga 2 , Clarice Lee 1 , Carolyn Samer 3 , Songyi Li 1 , Lucy J Meehan 1 , Hamish EG McWilliam 1 4 , Jose A Villadangos 1 4 , Nicholas A Gherardin 1 , Allison Abendroth 3 , Barry Slobedman 3 , Alexandra J Corbett 1 , Jim McCluskey 1 , Jamie Rossjohn 2 5 , Zhenjun Chen 1 , Wael Awad 2 , Michael Souter 1
  1. Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  2. Department of Biochemistry and Molecular Biology and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  3. Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
  4. Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
  5. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, United Kingdom

The major histocompatibility complex (MHC) class I related molecule 1 (MR1) presents riboflavin derived metabolites to mucosal-associated invariant T (MAIT) cells. Unlike MHC-I, MR1 exhibits limited polymorphism within the human population. As such, MAIT cells recognize MR1 in a highly conserved manner. Recently, five MR1 alleles (MR1*02-06) were described that alter the mature protein of MR1 in comparison to wild type MR1*01. Here, we have explored the impact of allelic variation of MR1 on expression and function. Through the generation of MR1 overexpressing cell lines and soluble MR1 proteins, we characterized the structure and function of each variant. We found the expression, antigen presentation and T cell activation capacity varied significantly among MR1 variants. In particular, we observed that MR1*05 had severely attenuated surface expression and impaired ability to activate primary MAIT cells. Structural investigation and mutagenesis suggests that a single mutation within MR1*05 is primarily responsible for the observed reduction in MR1*05 function and this is likely mediated by a loss of stability in the endoplasmic reticulum. Consistent with our previous findings, we confirmed that MR1*04, bearing the Arg9His mutation preferentially presents the B6 vitamer, pyridoxal, and can activate a population of diverse MR1-reactive T cells. Together, our data demonstrate that allelic variation can dramatically alter the function of MR1 and may have important implications for MAIT and other MR1-reactive T cell development and immunity.