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

Sushma Anand, Dene R. Littler, Jesse I. Mobbs, Asolina Braun, Daniel G. Baker, Luke Tennant, Anthony W. Purcell, Julian P. Vivian, Jamie Rossjohn

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number104930
Number of pages10
JournalJournal of Biological Chemistry
Volume299
Issue number7
DOIs
Publication statusPublished - Jul 2023

Keywords

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

Cite this