Loss of CD8+ MAIT cells drives reduced MAIT cytotoxicity in obesity – implications for obesity-associated cancer

The Physiology of Obesity: From Mechanisms to Medicine (University of Nottingham, UK) (2025) Proc Physiol Soc 65, C07

Oral Communications: Loss of CD8+ MAIT cells drives reduced MAIT cytotoxicity in obesity – implications for obesity-associated cancer

Féaron C. Cassidy1, Odhran K. Ryan2, Eimear Ryan2, Ronan Bergin2, Donal O'Shea3, Andrew E. Hogan4

1Maynooth University & Karolinska Institutet Ireland & Sweden, 2Maynooth University Ireland, 3St Vincent’s University Hospital & University College Dublin Ireland, 4Maynooth University & National Children’s Research Centre Ireland

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Introduction

Mucosal Associated Invariant T (MAIT) cells are innate, unconventional T cells with specific recognition for antigen presented by MR1 (MHC class-I like molecule). MAIT cells have highly efficient cytotoxic capacity against infected and malignant cells. Previous reports have noted MAIT disruption in the context of obesity and obesity-related morbidities.

Aim

Considering this with the increased risk of cancer in people with obesity we investigated MAIT cytotoxic function in the context of obesity.

Method

MAIT cells were expanded and isolated from the peripheral blood of donors with and without obesity who provided explicit consent in accordance with full ethical approval. MAIT cell characteristics that pertain to cancer risk were assessed in the overall MAIT cell population as well as in previously described phenotypic subsets. Flow cytometry was used to phenotype and measure degranulation (CD107a expression) in MAIT cells. Phenotype was further characterised using RNAseq, while cytotoxicity was confirmed with calcein AM assays. Sufficient power was confirmed with power analyses. All statistical analyses were confirmed appropriate to the nature of the individual dataset (normality, variance, paired etc.) using Graphpad Prism, which was also used to analyse and plot the datasets.

Results

Here we demonstrate a markedly reduced ability for tumour lysis by MAIT cells from people with obesity. We further uncover the importance of MAIT cell subsets in obesity-associated MAIT dysfunction, including cytotoxicity. We show that a MAIT subpopulation (CD4+CD8) that is exceedingly rare in lean, metabolically healthy donors makes up a significant proportion of MAIT cells in people with obesity, and that this shift is physiologically relevant. We find that MAIT CD4+ and CD8+ subsets differ in their functionality, with CD8+ MAITs responsible for cytotoxicity.  We find the CD8+ compartment of MAITs to be preferentially depleted in people with obesity, and that this change is sufficient to account for previously described obesity-associated MAIT phenotypes, and for the deficiency in MAIT oncolytic function presented here.

Summary

We show for the first time that MAIT cell cytotoxicity is reduced in people with obesity, and that this is driven by a shift in MAIT CD4:CD8.

Conclusion

These findings are of crucial importance to progressing understanding of cancer risk reduction in the context of obesity, and will have critical implications for MAIT cell therapy development.



Where applicable, experiments conform with Society ethical requirements.

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