Drugs/Drug analogues modulate MAIT cell function in an MR1-dependent manner — ASN Events
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Drugs/Drug analogues modulate MAIT cell function in an MR1-dependent manner (#98)

Sidonia BG Eckle 1 , Andrew N Keller 2 , Bronwyn S Meehan 1 , Victoria Hughes 2 , Lyudmila Kostenko 1 , Zhenjun Chen 1 , Troi Pediongco 1 , Lars Kjer-Nielsen 1 , Alex J Corbett 1 , Weijun Xu 3 , Jeffrey Mak 3 , Ligong Liu 3 , David Fairlie 3 , Jamie Rossjohn 2 4 5 , James McCluskey 1
  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
  2. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  3. Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  4. Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia
  5. Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK

Mucosal Associated Invariant T (MAIT) cells are an abundant subset of T cells, whose T cell receptor is restricted by the monomorphic MHC class I related molecule MR1 [1]. Acting as signature biomarkers of microbial infection, stimulating MAIT cell antigens (Ags), such as 5-OP-RU, originate from the microbial biosynthesis of riboflavin (vitamin B2) [2]. MR1 also binds non-stimulating Ags, which act as competitive inhibitors of stimulating Ags. 6-formyl-pterin (6-FP), a photodegradation product of folic acid (vitamin B9) and artificial analogues of 6-FP, such as acetyl-6-FP, are potent inhibitors [3,4].

Given the small molecule nature of MR1 ligands identified thus far we reasoned that drugs and drug analogues could represent a source of exogenous MR1 ligands. Indeed when screening a focussed library of drugs and drug analogues we identified a number of novel MR1 ligands, including 3- and 5-formyl salicyclic acid, analogues of aspirin. Some of these drugs and drug analogues potently upregulated MR1 and inhibited human and mouse MAIT cell activity in response to 5-OP-RU, as determined by in vitro analyses. Furthermore, these drugs and drug analogues acted in a dose dependent manner as competitive inhibitors of human MAIT cells stimulated with 5-OP-RU to proliferate and to produce IFNγ and TNFα cytokines ex vivo. Additionally, a drug and metabolites thereof strongly activated a subset of MAIT cells in a dose-dependent and MR1-restricted manner.

Thus MR1 has the potential to accommodate a range of structurally distinct ligands that have the capacity to directly modulate MAIT cell function by either competitively inhibiting MAIT cell activation or activating subsets of MAIT cells. These findings suggest that widely used drugs can inadvertently modulate MAIT cell function. Given the monomorphic and evolutionary conserved nature of the MAIT-MR1 axis this effect has a global impact.

  1. Treiner, E., Duban, L., Bahram, S., Radosavljevic, M., Wanner, V., Tilloy, F., Affaticati, P., Gilfillan, S., and Lantz, O. (2003) Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164-169
  2. Corbett, A. J., Eckle, S. B., Birkinshaw, R. W., Liu, L., Patel, O., Mahony, J., Chen, Z., Reantragoon, R., Meehan, B., Cao, H., Williamson, N. A., Strugnell, R. A., Van Sinderen, D., Mak, J. Y., Fairlie, D. P., Kjer-Nielsen, L., Rossjohn, J., and McCluskey, J. (2014) T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361-365
  3. Kjer-Nielsen, L., Patel, O., Corbett, A. J., Le Nours, J., Meehan, B., Liu, L., Bhati, M., Chen, Z., Kostenko, L., Reantragoon, R., Williamson, N. A., Purcell, A. W., Dudek, N. L., McConville, M. J., O'Hair, R. A., Khairallah, G. N., Godfrey, D. I., Fairlie, D. P., Rossjohn, J., and McCluskey, J. (2012) MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717-723
  4. Eckle, S. B., Birkinshaw, R. W., Kostenko, L., Corbett, A. J., McWilliam, H. E., Reantragoon, R., Chen, Z., Gherardin, N. A., Beddoe, T., Liu, L., Patel, O., Meehan, B., Fairlie, D. P., Villadangos, J. A., Godfrey, D. I., Kjer-Nielsen, L., McCluskey, J., and Rossjohn, J. (2014) A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. The Journal of experimental medicine 211, 1585-1600