Targeting the MR1-MAIT cell axis improves vaccine efficacy and affords protection against viral pathogens Journal Articles uri icon

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  • Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. Additionally, MAIT cells sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unclear. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster virus-specific CD8+ T cell responses, and potentiate heterosubtypic anti-influenza protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency and Toll-like receptor 3 and type I interferon receptor signaling. The observed phenomenon was reproducible in female and male mice, and in both young and old animals. It could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses.


  • Rashu, Rasheduzzaman
  • Ninkov, Marina
  • Wardell, Christine M
  • Benoit, Jenna M
  • Wang, Nicole I
  • Meilleur, Courtney E
  • D’Agostino, Michael R
  • Zhang, Ali
  • Feng, Emily
  • Saeedian, Nasrin
  • Bell, Gillian I
  • Vahedi, Fatemeh
  • Hess, David A
  • Barr, Stephen D
  • Troyer, Ryan M
  • Kang, Chil-Yong
  • Ashkar, Ali A
  • Miller, Matthew S
  • Haeryfar, SM Mansour

publication date

  • June 2023