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Peer-reviewedCC BYNature Communications

Human neonatal MR1T cells have more diverse TCR repertoires but reduced bacterial recognition than adult MR1T cells

  • Dylan C. Kain1,2,3
  • Wael Awad4
  • GW McElfresh5
  • Meghan E. Cansler2
  • Gwendolyn M. Swarbrick2
  • Kean Chan Yew Poa4
  • Conor McNeice4
  • Gregory J. Boggy5
  • Katherine H. Rott2
  • Megan D. Null2
  • David Michael Lewinsohn6,3
  • Jamie Rossjohn4,7
2 more authors
  • Benjamin N. Bimber5,8
  • Deborah A. Lewinsohn6,3
8 affiliations
  1. 1Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, ON, Canada
  2. 2Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA
  3. 3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Oregon Health & Science University, Portland, OR, USA
  4. 4Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  5. 5Oregon National Primate Research Center, OHSU, Beaverton, OR, USA
  6. 6Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA. [email protected]
  7. 7Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff, UK
  8. 8Vaccine and Gene Therapy Institute, OHSU, Beaverton, OR, USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{kain2026human,
  title = {{Human neonatal MR1T cells have more diverse TCR repertoires but reduced bacterial recognition than adult MR1T cells}},
  author = {Dylan C. Kain and Wael Awad and GW McElfresh and Meghan E. Cansler and Gwendolyn M. Swarbrick and Kean Chan Yew Poa and Conor McNeice and Gregory J. Boggy and Katherine H. Rott and Megan D. Null and David Michael Lewinsohn and Jamie Rossjohn and Benjamin N. Bimber and Deborah A. Lewinsohn},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74998-7},
  url = {https://doi.org/10.1038/s41467-026-74998-7},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Human neonatal MR1T cells have more diverse TCR repertoires but reduced bacterial recognition than adult MR1T cells
AU  - Dylan C. Kain
AU  - Wael Awad
AU  - GW McElfresh
AU  - Meghan E. Cansler
AU  - Gwendolyn M. Swarbrick
AU  - Kean Chan Yew Poa
AU  - Conor McNeice
AU  - Gregory J. Boggy
AU  - Katherine H. Rott
AU  - Megan D. Null
AU  - David Michael Lewinsohn
AU  - Jamie Rossjohn
AU  - Benjamin N. Bimber
AU  - Deborah A. Lewinsohn
PY  - 2026
DA  - 2026/06/29
JO  - Nature Communications
DO  - 10.1038/s41467-026-74998-7
UR  - https://doi.org/10.1038/s41467-026-74998-7
AB  - 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.
SN  - 2041-1723
ER  -