Complimentary electrostatics dominate T Cell Receptor binding to a psoriasis-associated-peptide-antigen presented by Human Leukocyte Antigen (HLA) C*06:02.

Psoriasis is a chronic skin disease characterised by hyperproliferative epidermal lesions infiltrated by autoreactive T cells. Individuals expressing the Human Leukocyte antigen (HLA) C*06:02 allele are at highest risk for developing psoriasis. An autoreactive T cell clone (termed Vα3S1/Vβ13S1) isolated from psoriatic plaques is selective for HLA-C*06:02-presenting a peptide derived from the melanocyte-specific auto-antigen ADAMTSL5 (VRSRRCLRL). Here we determine the crystal structure of this psoriatic TCR-HLA-C*06:02- ADAMTSL5 complex with a stabilised peptide. Docking of the TCR involves an extensive complementary charge network formed between negatively charged TCR residues interleaving with exposed arginine residues from the self-peptide and the HLA-C*06:02 α1 helix. We probed these interactions through mutagenesis and activation assays. The charged interface spans the polymorphic region of the C1/C2 HLA group. Notably the peptide binding groove of HLA C*06:02 appears exquisitely suited for presenting highly charged Arg-rich epitopes recognised by this acidic psoriatic TCR. Overall, we provide a structural basis for understanding engagement of melanocyte antigen-presenting cells by a TCR implicated in psoriasis, while simultaneously expanding our knowledge of how TCRs engage HLA-C.