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- Title
Targeting the MR1-MAIT cell axis improves vaccine efficacy and affords protection against viral pathogens.
- Authors
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, S. M. Mansour
- Abstract
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. Author summary: Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved lymphocytes that recognize and respond to bacterial metabolites presented by an antigen-presenting molecule called MR1. Although MAIT cells have been implicated in antiviral immunity, whether their stimulation by MR1 ligands can improve immune responses to viral invaders has been unclear. We addressed this question in several mouse models and primary and prime-boost immunization strategies against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that an MR1 ligand called 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) can be incorporated into select vaccine formulations to expand tissue MAIT cells and reprogram them towards a pro-inflammatory phenotype, to enhance conventional virus-specific T cell responses, and to promote protection against influenza A viruses (IAVs). We found this phenomenon to be dependent upon the in vivo engagement of a pathogen recognition receptor called Toll-like receptor 3 as well as the receptor for type I interferons. Also importantly, MAIT cell proliferation in response to an IAV strain and 5-OP-RU could be phenocopied in a human white blood cell culture system. We propose that 5-OP-RU, and potentially other MR1 ligands, may be used to increase the efficacy of certain vaccines against respiratory viral infections.
- Subjects
VITAMIN B2; SARS-CoV-2; T cells; INTERFERON receptors; VACCINE effectiveness; MONONUCLEAR leukocytes; CELL culture; LEUCOCYTES; TYPE I interferons
- Publication
PLoS Pathogens, 2023, Vol 18, Issue 6, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1011485