Psoriasis is a T cell-mediated autoimmune disease without a cure. The major risk-associated psoriasis susceptibility gene encodes for the human leukocyte antigen C*06:02 (HLA-Cw6). Around half of the patients carry this allele encoding a HLA class I molecule which initiates immune responses by presenting a vast array of short peptide antigens (collectively known as the immunopeptidome) to CD8 T cells and NK cells.
It is unclear which pathogen-derived or self peptides presented by HLA-Cw6 are the prevalent trigger of T cell responses in psoriasis. Therefore, we generated immunopeptidomics data from skin-derived HLA-Cw6+ cell lines (>24,000 peptides) and a newly generated HLA-Cw6Tg mouse model in conjunction with the imiquimod-induced mouse model of psoriasis (>4,000 peptides) thus identifying a set of peptides of high relevance to finding universal molecular triggers of psoriasis. Strikingly, 58% of HLA-I characteristic 9-mer peptides exclusive to mouse HLA-Cw6Tg skin, were either identical or very similar (1 amino acid change) to peptides that we detected in human HLA-Cw6+ melanocyte/keratinocytes.
The high reoccurrence rate of lesions in the same location together with the understanding that the T cell compartment drives disease suggests the involvement of skin-resident memory T cells in psoriasis. To interrogate the T cell – antigen interactions, we performed single cell T cell receptor sequencing and clonal analysis of the epidermal CD8 T cells from lesional and non-lesional biopsies of HLA-Cw6+/HLA-Cw6- patients. We are currently screening these T cell receptors against our candidate peptides to establish dominant peptide triggers of psoriasis broadly recognized by autoreactive CD8 T cells.
We conclude that applying antigen discovery to clinical samples and our new preclinical HLA-Cw6Tg mouse model is a valid means to study the psoriasis-relevant immunopeptidome. Defining broadly recognised HLA-Cw6-restricted peptide antigens in psoriasis, will facilitate therapeutic approaches to develop tolerisation strategies with the potential to achieve long-lasting remission.