6V18

immune receptor complex

Summary for 6V18

• Entry DOI: 10.2210/pdb6v18/pdb
• Related: 6V0Y 6V13 6V15
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen, DRB1-4 beta chain, Fibrinogen beta, ... (8 entities in total)
• Functional Keywords: immune receptor, complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 98418.23

Authors

Lim, J.J.,Rossjohn, J. (deposition date: 2019-11-20, release date: 2020-11-25, Last modification date: 2024-11-06)

Primary citation

Lim, J.J.,Jones, C.M.,Loh, T.J.,Ting, Y.T.,Zareie, P.,Loh, K.L.,Felix, N.J.,Suri, A.,McKinnon, M.,Stevenaert, F.,Sharma, R.K.,Klareskog, L.,Malmstrom, V.,Baker, D.G.,Purcell, A.W.,Reid, H.H.,La Gruta, N.L.,Rossjohn, J.
The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR.
Sci Immunol, 6:-, 2021

PubMed Abstract: 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.

PubMed: 33863750
DOI: 10.1126/sciimmunol.abe0896

Experimental method

X-RAY DIFFRACTION (2.35 Å)