Psoriasis is a T cell-mediated autoimmune disease for which the human leukocyte antigen class I molecule HLA-C*06:02 (HLA-Cw6) is a major genetic risk factor. HLA-Cw6 presents peptide antigens to CD8+ T cells. We have previously isolated HLA-Cw6 ligands to identify the sequences and consensus binding motif of peptides presented by HLA-Cw6. CD8+ skin resident memory T cells (CD8+ TRM) are central mediators of pathology. We hypothesise that HLA-Cw6-restricted antigens presented in epidermis likely elicit autoreactive CD8+ TRM responses that contribute to the development of psoriasis. In this project, we focused on the characterization of psoriatic lesional T cells by sequencing single cell TCR of epidermal CD8+ TRM and analyzing by TCR_Explore. On average, 230 T cells from psoriatic lesional and 198 T cells from non-lesional 3mm biopsies were isolated and sorted per patient (n=10). A total of 64 expanded TCR clonotypes were discovered in lesional epidermis of six psoriasis patients. In one HLA-Cw6+ guttate psoriasis patient, 10 unique expanded TCR clonotypes were identified in lesional epidermis, and the highest expanded TCR clone occupied up to 22% of total cells sequenced. Additionally, common beta chain usages of sequenced TCRs (BV2, BV7 and BV20-1) were identified in lesional epidermis across three HLA-Cw6+ patients, which accorded with previous literatures of prevalent TCR beta chains in psoriasis. Importantly, all lesional expanded TCR clones were not found to be expanded in peripheral T cells and typically were not found in non-lesional T cells. Additionally, RNA-seq for circulating CD8+ T cells from patient peripheral blood were performed by BD Rhapsody and analysed by a bespoke novel tool 'STEGO.R'.
The here identified expanded TCRs will be of great use for further peptide specificity screening to identify potential dominant HLA-Cw6 epitopes that elicit autoimmunity and drive expansion of TCR clonotypes across a number of HLA-Cw6+ psoriasis patients.