A new study in Cell Reports Methods by Cell Press takes immunopeptidomics in an exciting new direction. While traditional approaches focus on peptides presented by classical MHC molecules, the researchers asked a different question: how can we profile non-peptidic antigens?

This study expands the field by profiling small-molecule ligands bound to MR1, a non-classical MHC class I–like molecule. Using a clever cross-linking approach, the team covalently stabilised the fleeting interaction between MR1 and vitamin B6–derived metabolites, making these complexes detectable by mass spectrometry.

They then harnessed 𝗣𝗘𝗔𝗞𝗦 𝗦𝘁𝘂𝗱𝗶𝗼 𝘀𝗼𝗳𝘁𝘄𝗮𝗿𝗲 to identify these small molecules as post-translational modifications on a reporter peptide, pinpointing their mass, composition, and specificity. This workflow opens new possibilities for studying unconventional antigen presentation and T-cell recognition.

Read the full article here: Schmidlin, T., Behiry, E., Thomas, H., Dolton, G., Marino, F., Hasan, S., ... & Ternette, N. (2025). MR1-ligand cross-linking identifies vitamin B6 metabolites as TCR-reactive antigens. Cell Reports Methods. doi:10.1016/j.crmeth.2025.101120