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

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.

Comparative single‐cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS‐CoV‐2 infection

“…Our study uncovers significant transcriptional changes in MAIT cells following In‐Vac administration, with an augmentation in intercellular communication facilitated by these cells. This is consistent with the notion that MAIT cells are critical targets to enhance the efficacy of diverse vaccines and vaccine‐induced immunity 59,77–80 . Furthermore, our study reveals that MAIT cells could be activated following In‐Vac administration through their expression of IL15 receptor and cell–cell interactions 81 .…”

“…This is consistent with the notion that MAIT cells are critical targets to enhance the efficacy of diverse vaccines and vaccine-induced immunity. 59,[77][78][79][80] Furthermore, our study reveals that MAIT cells could be activated following In-Vac administration through their expression of IL15 receptor and cell-cell interactions. 81 Additionally, IL15 expression on MAIT cells has the capacity to activate T cells and B cells.…”

Diverging patterns in innate immunity against respiratory viruses during a lifetime: lessons from the young and the old

“…In one murine study, the MAIT ligand 5-OP-RU was administered together with intraperitoneal influenza, which led to MAIT cell proliferation and accumulation in multiple tissues, including the lungs of both young and old mice [ 186 ]. This was associated with heterosubtypic protection from subsequent influenza A virus challenge and similar MAIT cell induction was seen when 5-OP-RU was administered together with an intranasal influenza vaccine or an intramuscular recombinant vesicular stomatitis virus-based SARS-CoV-2 vaccine.…”

Current Perspectives and Challenges of MAIT Cell-Directed Therapy for Tuberculosis Infection

“…MAIT cells that were challenged with S. typhimurium and adoptively transferred to immunodeficient mice were protective against lethal Legionella infection, while vaccination of mice by antigen priming prior to infection also enhanced protection [72]. Using a mouse model, the incorporation of the MR1 ligand, 5-OP-RU into vaccine formulations enhanced the pro-inflammatory response of MAIT cells against the influenza virus, effectively controlling the infection [73]. Moreover, the efficacy of this approach was maintained in young and old mice (keeping in mind that MAIT cell numbers naturally decline in old age) and this effect was replicated in human blood cultures.…”