A transgenic mouse allows characterization of the HLA-C∗06:02 immunopeptidome in a model of psoriasis

Psoriasis vulgaris is a T-cell-mediated autoimmune skin condition affecting around 1 in 50 people worldwide. Although advanced immunomodulatory therapeutic options have become available in recent years, ongoing disease suppression is still required, with no curative treatment available to date. The HLA class I allele HLA-C∗06:02 is the main genetic risk determinant of psoriasis. HLA-C molecules present peptide antigens to CD8⁺ T cells and NK cells that in turn elicit and perpetuate the immune response, yet little is known about the ligands presented by HLA-C∗06:02. To gain an understanding of which HLA-C∗06:02-restricted peptides are presented by epidermal cell populations and might be initiators of the autoimmune response in psoriasis, we have conducted an in depth immunopeptidomic analysis of keratinocyte and melanocyte cell lines positive for HLA-C∗06:02 and either HLA-C∗07:01 or HLA-C∗07:02. Furthermore, we introduce an HLA-C∗06:02-transgenic mouse, which, in conjunction with the imiquimod model of psoriasis, allowed us to assess the ex vivo immunopeptidome of HLA-C∗06:02 in psoriasiform skin. Overall, we identified 20,812 high-confidence HLA-C-bound peptide ligands derived from HLA-C∗06:02 and highly similar HLA-C∗07:01/02 immunopeptidomes. Thus, we present a comprehensive HLA-C in vitro immunopeptidomic dataset and an HLA-C∗06:02 ex vivo dataset of psoriasis-relevant peptide antigens that may inform the development of novel antigen-specific, curative therapeutic approaches in psoriasis.