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Peer-reviewedCC BY 4.0The Journal of Biological Chemistry

A murine MHC-Ib molecule, H2-Q9, drives peptide-centric T-cell receptor recognition of a viral antigen

  • Luke Tennant1
  • Chacko Jobichen1
  • Mai T. Tran1
  • Carine Farenc1
  • Stephanie Gras1
  • Aron E. Lukacher2
  • Lucy C. Sullivan3
  • Andrew G. Brooks3
  • Jamie Rossjohn1
  1. 1Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. 2Department of Cell and Biological Systems, Penn State College of Medicine, Hershey, Pennsylvania, USA
  3. 3Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
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Abstract

Highly polymorphic classical major histocompatibility complex class I (MHC-Ia) molecules present peptides to T-cell receptors (TCRs) expressed on CD8+ T-cells. In contrast, nonclassical MHC-Ib molecules are less polymorphic, and the structural principles governing their recognition by TCRs remain poorly understood. H2-Q9, a murine Qa-2 family MHC-Ib molecule presents the mouse polyomavirus-derived VP2.139 peptide (HALNVVHDW) to CD8+ T-cells, yet the molecular basis of TCR recognition of H2-Q9/peptide complexes remains unclear. Here, we characterized the interactions of two VP2.139-specific TCRs, C3K and AH1, with the VP2.139 peptide presented by H2-Q9, which showed similar moderate binding affinities. We then determined the structure of the TCR C3K bound to the VP2.139 peptide presented by H2-Q9. TCR C3K adopted a diagonal docking orientation and was tilted toward the N-terminal end of the peptide. The CDR3 loops formed extensive contacts with peptide positions P1–P8, whereas alanine-scanning mutagenesis at positions P1–P7 impaired TCR recognition. Structural comparison of H2-Q9 with classical murine MHC-Ia molecules identified substitutions in the α3-domain that alter the CD8-binding interface and may explain the previously observed absence of CD8 binding to H2-Q9. Together, these findings provide insight into antigen recognition by a monomorphic MHC-Ib molecule.

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Cite

BibTeXRIS
BibTeX
@article{tennant2026murine,
  title = {{A murine MHC-Ib molecule, H2-Q9, drives peptide-centric T-cell receptor recognition of a viral antigen}},
  author = {Luke Tennant and Chacko Jobichen and Mai T. Tran and Carine Farenc and Stephanie Gras and Aron E. Lukacher and Lucy C. Sullivan and Andrew G. Brooks and Jamie Rossjohn},
  journal = {The Journal of Biological Chemistry},
  year = {2026},
  month = sep,
  doi = {10.1016/j.jbc.2026.113574},
  url = {https://doi.org/10.1016/j.jbc.2026.113574},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A murine MHC-Ib molecule, H2-Q9, drives peptide-centric T-cell receptor recognition of a viral antigen
AU  - Luke Tennant
AU  - Chacko Jobichen
AU  - Mai T. Tran
AU  - Carine Farenc
AU  - Stephanie Gras
AU  - Aron E. Lukacher
AU  - Lucy C. Sullivan
AU  - Andrew G. Brooks
AU  - Jamie Rossjohn
PY  - 2026
DA  - 2026/09/17
JO  - The Journal of Biological Chemistry
DO  - 10.1016/j.jbc.2026.113574
UR  - https://doi.org/10.1016/j.jbc.2026.113574
AB  - Highly polymorphic classical major histocompatibility complex class I (MHC-Ia) molecules present peptides to T-cell receptors (TCRs) expressed on CD8+ T-cells. In contrast, nonclassical MHC-Ib molecules are less polymorphic, and the structural principles governing their recognition by TCRs remain poorly understood. H2-Q9, a murine Qa-2 family MHC-Ib molecule presents the mouse polyomavirus-derived VP2.139 peptide (HALNVVHDW) to CD8+ T-cells, yet the molecular basis of TCR recognition of H2-Q9/peptide complexes remains unclear. Here, we characterized the interactions of two VP2.139-specific TCRs, C3K and AH1, with the VP2.139 peptide presented by H2-Q9, which showed similar moderate binding affinities. We then determined the structure of the TCR C3K bound to the VP2.139 peptide presented by H2-Q9. TCR C3K adopted a diagonal docking orientation and was tilted toward the N-terminal end of the peptide. The CDR3 loops formed extensive contacts with peptide positions P1–P8, whereas alanine-scanning mutagenesis at positions P1–P7 impaired TCR recognition. Structural comparison of H2-Q9 with classical murine MHC-Ia molecules identified substitutions in the α3-domain that alter the CD8-binding interface and may explain the previously observed absence of CD8 binding to H2-Q9. Together, these findings provide insight into antigen recognition by a monomorphic MHC-Ib molecule.
SN  - 0021-9258
SN  - 1083-351X
ER  -