Human neonatal MR1T cells have diverse TCR usage, are less cytotoxic and are unable to respond to many common childhood pathogens

Kain, Dylan, Awad, Wael, McElfresh, GW, Cansler, Meghan, Swarbrick, Gwendolyn M., Yew Poa, Kean Chan, McNeice, Conor, Boggy, Gregory, Rott, Katherine, Null, Megan D, Lewinsohn, David, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Bimber, Benjamin N and Lewinsolm, Deborah 2025. Human neonatal MR1T cells have diverse TCR usage, are less cytotoxic and are unable to respond to many common childhood pathogens. [Online]. bioRxiv: OpenRxiv. Available at: https://doi.org/10.1101/2025.03.17.643805

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Abstract

Neonatal sepsis is a leading cause of childhood mortality. Understanding immune cell development can inform strategies to combat this. MR1-restricted T (MR1T) cells can be defined by their recognition of small molecules derived from microbes, self, and drug and drug-like molecules, presented by the MHC class 1-related molecule (MR1). In healthy adults, the majority of MR1T cells express an invariant α-chain; TRAV1-2/TRAJ33/12/20 and are referred to as mucosal-associated invariant T (MAIT) cells. Neonatal MR1T cells isolated from cord blood (CB) demonstrate more diversity in MR1T TCR usage, with the majority of MR1-5-OP-RU-tetramer(+) cells being TRAV1-2(-). To better understand this diversity, we performed single-cell-RNA-seq/TCR-seq (scRNA-seq/scTCR-seq) on MR1-5-OP-RU-tetramer(+) cells from CB (n=5) and adult participants (n=5). CB-derived MR1T cells demonstrate a less cytotoxic/pro-inflammatory phenotype, and a more diverse TCR repertoire. A panel of CB and adult MAIT and TRAV1-2(-) MR1T cell clones were generated, and CB-derived clones were unable to recognize several common riboflavin-producing childhood pathogens (S. aureus, S. pneumoniae, M. tuberculosis). Biochemical and structural investigation of one CB MAIT TCR (CB964 A2; TRAV1-2/TRBV6-2) showed a reduction in binding affinity toward the canonical MR1-antigen, 5-OP-RU, compared to adult MAIT TCRs that correlated with differences in β-chain contribution in the TCR-MR1 interface. Overall, this data shows that CB MAIT and TRAV1-2(-) MR1T cells, express a diverse TCR repertoire, a more restricted childhood pathogen recognition profile and diminished cytotoxic and pro-inflammatory capacity. Understanding this diversity, along with the functional ability of TRAV1-2(-) MR1T cells, could provide insight into increased neonatal susceptibility to infections.

Item Type:	Website Content
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI)
Publisher:	OpenRxiv
Date of Acceptance:	20 March 2025
Last Modified:	04 Sep 2025 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/180852

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