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.