Details

Autor(en) / Beteiligte

• Lim, Jia Jia
• Jones, Claerwen M
• Loh, Tiing Jen
• Ting, Yi Tian
• Zareie, Pirooz
• Loh, Khai L
• Felix, Nathan J
• Suri, Anish
• McKinnon, Murray
• Stevenaert, Frederik
• Sharma, Ravi K
• Klareskog, Lars
• Malmström, Vivianne
• Baker, Daniel G
• Purcell, Anthony W
• Reid, Hugh H
• La Gruta, Nicole L
• Rossjohn, Jamie

Titel

The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR

Ist Teil von

• Science immunology, 2021-04, Vol.6 (58)

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• Individuals expressing HLA-DR4 bearing the shared susceptibility epitope (SE) have an increased risk of developing rheumatoid arthritis (RA). Posttranslational modification of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, in T cell-mediated autoimmunity, the interplay between the HLA molecule, posttranslationally modified epitope(s), and the responding T cell repertoire remains unclear. In HLA-DR4 transgenic mice, we show that immunization with a Fibβ-74cit peptide led to a population of HLA-DR4 tetramer T cells that exhibited biased T cell receptor (TCR) β chain usage, which was attributable to selective clonal expansion from the preimmune repertoire. Crystal structures of pre- and postimmune TCRs showed that the SE of HLA-DR4 represented a main TCR contact zone. Immunization with a double citrullinated epitope (Fibβ-72,74cit ) altered the responding HLA-DR4 tetramer T cell repertoire, which was due to the P2-citrulline residue interacting with the TCR itself. We show that the SE of HLA-DR4 has dual functionality, namely, presentation and a direct TCR recognition determinant. Analogous biased TCR β chain usage toward the Fibβ-74cit peptide was observed in healthy HLA-DR4 individuals and patients with HLA-DR4 RA, thereby suggesting a link to human RA.