# Modulation of in vivo MAIT cell responses with diverse MR1 ligands

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $221,875

## Abstract

Project Summary
Pulmonary diseases are a major health concern, with pneumonia the leading infectious cause of mortality for
young children. Respiratory infections in early life are associated with increased susceptibility to asthma; an
inflammatory disorder that afflicts more than 250 million people each year and has increased in prevalence
during the past decade. However, the lack of vaccines for many of the pathogens that cause pneumonia and the
emergence of antibiotic resistant bacteria necessitate alternative approaches. Mucosal-associated invariant T
(MAIT) cells comprise a substantial effector population within human lungs, reaching up to 9% of pulmonary T
cells in healthy individuals. MAIT cells recognize microbial derivatives of riboflavin (vitamin B2) synthesis
presented by the MHC class-I related (MR1) molecule. Due to the broad conservation of this biosynthetic
pathway among bacteria and fungi, MAIT cells promote immunity to a wide array of respiratory pathogens. MAIT
cells have also been implicated in preventing asthma and reducing airway inflammation. However, in addition to
presenting derivatives of vitamin synthesis, recent work has demonstrated that MR1 can also bind drugs and
drug metabolites that can either be agonists or non-agonists of MAIT cells, suggesting that drugs may hinder
MR1-mediated presentation of endogenous microbial metabolites, which could have implications for the
susceptibility to pneumonia or asthma. While derivatives of riboflavin synthesis increase MAIT cell abundance
and cytokine production in vivo, the instability of these molecules results in rapid degradation under physiological
conditions, limiting their therapeutic potential. We will perform the first evaluation of how MR1 binding drugs
impact the development of MAIT cells and the first in vivo assessment of how non-vitamin derived MR1 ligands
affect MAIT cell responses to physiologically relevant pulmonary conditions. We will also perform the most
extensive virtual screen to date for novel MAIT cell agonists using Reactive Docking to simulate the formation of
a Schiff base with K43 of MR1 – a key characteristic of the strongest known MAIT cell agonists the promotes
MR1 folding for surface expression. Following validation of MR1 binding and MAIT cell agonistic activity in vitro,
the immunomodulatory effects of these novel agonists will be established in vivo. We hypothesize that we will
identify novel MAIT cell agonists that enhance pulmonary immunity, while administration of non-agonistic MR1
binding drugs can inhibit the development and function of MAIT cells in vivo.

## Key facts

- **NIH application ID:** 10626969
- **Project number:** 5R21AI171697-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Michael George Constantinides
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $221,875
- **Award type:** 5
- **Project period:** 2022-05-24 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626969

## Citation

> US National Institutes of Health, RePORTER application 10626969, Modulation of in vivo MAIT cell responses with diverse MR1 ligands (5R21AI171697-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10626969. Licensed CC0.

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