Microbiome Determinants of MAIT cell phenotype and function

PROJECT OVERVIEW

The human gut microbiome is a complex ecosystem, made up of all domains of life (bacteria, archaea, eukarya), and containing approximately the same number of cells as are encountered in the adult human body [1]. It is also highly diverse, influenced by our environment, and known to vary substantially both between individuals and between human populations [2].

Close interaction between the gut microbiome and the human immune system means such variation also has the potential to influence the way the immune system develops and functions in health and disease [3]. However, many of the molecular and cellular pathways that underpin most microbe-immune interactions are yet to be fully described.

This project has a specific focus on how the gut microbiome interacts with a single immune cell population. Mucosal associated invariant T (MAIT) cells are a critical innate-like T cell population that is abundant at barrier surfaces, but that can also constitute up to 10% of circulating T cells. MAIT cells are characterized by their semi-invariant T cell receptor, which primarily recognizes microbially produced metabolites, presented via the MHC class 1 related protein MR1.

In addition to TCR-mediated pathways, MAIT cells can also be activated via endogenous cytokine production, and the relative balance of these two sources of stimuli is critical in determining the widespread variation that is observed in MAIT cell phenotype and function [4]. Understanding how microbiome diversity directly and indirectly influences MAIT cells via these two pathways is therefore critical for understanding how the gut microbiome can influence this important cell population.

Building on existing collaborations between the Johnson, Klenerman, and Provine labs, this project will leverage existing opportunities to study the impact of gut microbiome variation on MAIT cell phenotype and function. This will include metagenomic characterization of gut microbiome variation in humans and concurrent immune phenotyping of MAIT and related T cell populations in blood and tissues. There will subsequently be the opportunity to reductively explore relevant microbe-MAIT associations in vitro and in in vivo model systems.

Overall, this project would suit someone with a passion for understanding, at a mechanistic level, how the gut microbiome interacts with the human immune system to shape response to immune challenge and the development of inflammatory disease.

KEYWORDS

Gut microbiome, Mucosal Associated Invariant T (MAIT) cells,

TRAINING OPPORTUNITIES

This project comes with opportunities to gain complementary skills in both wet and dry lab research, with a specific balance to suit the developing interests of the candidate.

This includes acquiring expertise in bioinformatic approaches for the analysis and integration of microbiome and host multi-omic data, as well as becoming an active member of the Data Science research theme within the Kennedy Institute of Rheumatology (KIR).

Wet lab approaches will initially focus on high-dimensional flow cytometry methods for MAIT cell characterization, as well as methods for quantification of MR1/MAIT ligands and studying their in vitro effects.

In vivo models will take advantage of the state-of-the art germ-free facility within the KIR, with opportunities to develop defined microbial consortia and validate their ability to impact MAIT cell phenotype in the gut.

KEY PUBLICATIONS

1. Sender R, Fuchs S, Milo R. Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLoS Biology. 2016;14(8):e1002533. doi:10.1371/journal.pbio.1002533
2. Rosenberg, E. Diversity of bacteria within the human gut and its contribution to the functional unity of holobionts. npj Biofilms Microbiomes 10, 134 (2024). https://doi.org/10.1038/s41522-024-00580-y
3. Iliev, I.D., Blander, J.M., Collins, N. et al. Microbiota-mediated mechanisms of mucosal immunity across the lifespan. Nat Immunol 26, 1645–1659 (2025). https://doi.org/10.1038/s41590-025-02281-w
4. Provine, N.M., Klenerman P., Mait cells in health and diseases. Annual Review of Immunology 38, 203-228 (2020) https://doi.org/10.1146/annurev-immunol-080719-015428

THEMES

Microbiome, Inflammation, Interacting Systems

CONTACT INFORMATION OF ALL SUPERVISORS

Jethro Johnson 

Paul Klenerman 

Nicholas Provine