Arginine (Di)methylated Human Leukocyte Antigen Class I Peptides Are Favorably Presented by HLA-B*07

Alterations in protein
post-translational modification (PTM) are
recognized hallmarks of diseases. These modifications potentially
provide a unique source of disease-related human leukocyte antigen
(HLA) class I-presented peptides that can elicit specific immune responses.
While phosphorylated HLA peptides have already received attention,
arginine methylated HLA class I peptide presentation has not been
characterized in detail. In a human B-cell line we detected 149 HLA
class I peptides harboring mono- and/or dimethylated arginine residues
by mass spectrometry. A striking preference was observed in the presentation
of arginine (di)­methylated peptides for HLA-B*07 molecules, likely
because the binding motifs of this allele resemble consensus sequences
recognized by arginine methyl-transferases. Moreover, HLA-B*07-bound
peptides preferentially harbored dimethylated groups at the P3 position,
thus consecutively to the proline anchor residue. Such a proline-arginine
sequence has been associated with the arginine methyl-transferases
CARM1 and PRMT5. Making use of the specific neutral losses in fragmentation
spectra, we found most of the peptides to be asymmetrically dimethylated,
most likely by CARM1. These data expand our knowledge of the processing
and presentation of arginine (di)­methylated HLA class I peptides and
demonstrate that these types of modified peptides can be presented
for recognition by T-cells. HLA class I peptides with mono- and dimethylated
arginine residues may therefore offer a novel target for immunotherapy.