Simplifying principles underlying the highly complex peptide motif of the promiscuous chicken MHC class I molecule, BF2*21:01.

BF2*21:01, the chicken MHC class I molecule from the B21 haplotype, accommodates many peptide anchor combinations yet shows strong preferences that shape high-frequency major peptides.

• Why it matters: Classical MHC class I molecules differ in how broadly they present peptides, and understanding how promiscuous generalists like BF2*21:01 balance breadth with specificity is key for predicting immune targets.
• What they did: Using in vitro refolding with peptides and peptide libraries, thermostability testing, crystal structures, and immunopeptidomics of a chicken B21 cell line, the study mapped how anchor positions P2 and Pc-2 and Pc influence binding.
• The result: The data show flexible accommodation at P2/Pc-2 and Pc alongside marked preferences for peptide length, specific anchor amino acids, and coordinated residue combinations at P2/Pc-2 and P3/Pc-3, enabling prediction of pathogen peptides with stable binding and informing improved peptide prediction methods.

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