Lightning Talk (10 min oral) The 48th Lorne Conference on Protein Structure and Function 2023

Post-translational modification autoantigen-mediated T cell Immunity (#29)

Jia Jia Lim 1 , Claerwen M. Jones 1 , Tiing Jen Loh 1 , Nathan J. Felix 2 , Anish Suri 2 , Murray Mackinnon 2 , Frederick Stevenaert 3 , Ravi K. Sharma 4 , Lars Klareskog 4 , Vivianne Malmstrom 4 , Daniel G. Baker 2 , Anthony W. Purcell 1 , Hugh H. Reid 1 , Nicole L. La Gruta 1 , Jamie Rossjohn 1 5
  1. Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VICTORIA, Australia
  2. Janssen Research & Development, LLC, Horsham, Philadelphia, Pennsylvania, USA
  3. Janssen Research & Development, Turnhoutseweg 30, BE-2340, Beerse, Belgium
  4. Rheumatology Division, Department of Medicine, Karolinska Institute, Karolinska University Hospital 17177, Stockholm, Sweden
  5. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, , Cardiff CF14 4XN, UK

The autoreactive T cell repertoire driving disease activity in rheumatoid arthritis (RA) includes CD4+ T cells that recognize HLA-DRB1 presenting post-translational modified self-antigens. Some HLA-DRB1 alleles have a shared susceptibility epitope associated with increased RA incidence. For example, certain post-translational modifications (PTM) of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, the interplay between the HLA molecule, post-translationally modified epitope and the responding T cell repertoire remain unclear.

 

To understand the molecular basis of the citrullinated self-epitope, HLA-DR4, and CD4 T cell, we synthesized citrullinated fibrinogen peptide, which is found abundantly in joint synovium of RA patient, and investigated structurally their impact on HLA-DR4 recognition. Using combinational techniques including transgenic mouse model, FACS analyses, biochemical analyses and X-ray crystallography, we analysed the CD4+ TCR repertoire of HLA-DR4 presenting citrullinated epitope, affinities, and structure of multiple T cell receptors (TCRs) derived from humanized mice reactive with citrullinated peptides presented by HLA-DR4. TCR repertoire analysis revealed a citrullinated antigen-specific motif, conserved in both mice and humans. Crystal structures revealed duality function of shared epitope of HLA-DR4 in presenting citrullinated epitope, as well as direct contact with the TCR. This suggest that HLA-DRB1 alleles possess the shared epitope are contributed to the development of RA through both binding of stimulatory peptide epitopes and direct contact with a biased set of TCRs.