Complimentary electrostatics dominate T-cell receptor binding to a psoriasis-associated peptide antigen presented by human leukocyte antigen C∗06:02

J Biol Chem. 2023 Jul;299(7):104930. doi: 10.1016/j.jbc.2023.104930. Epub 2023 Jun 15.

Abstract

Psoriasis is a chronic skin disease characterized 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 autoantigen ADAMTSL5 (VRSRRCLRL). Here we determine the crystal structure of this psoriatic TCR-HLA-C∗06:02 ADAMTSL5 complex with a stabilized 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 recognized by this acidic psoriatic TCR. Overall, we provide a structural basis for understanding the engagement of melanocyte antigen-presenting cells by a TCR implicated in psoriasis while simultaneously expanding our knowledge of how TCRs engage HLA-C.

Keywords: HLA-C∗06:02; T-cell receptor; antigen presentation; autoimmunity; major histocompatibility complex (MHC); psoriasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins
  • HLA-C Antigens*
  • Humans
  • Peptides / chemistry
  • Psoriasis* / pathology
  • Receptors, Antigen, T-Cell / genetics
  • Static Electricity

Substances

  • HLA-C Antigens
  • Peptides
  • Receptors, Antigen, T-Cell
  • ADAMTSL5 protein, human
  • ADAMTS Proteins