Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Cross-reactivity of CD4+ gluten-reactive TCRs in Celiac Disease (#107)

Laura Ciacchi 1 2 , Carine Farenc 1 2 , Shiva Dahal-Koirala 3 4 , Jan Petersen 1 2 , Melinda Hardy 5 6 , Jason Tye-Din 5 6 7 , Ludvig M Sollid 3 4 , Hugh H Reid 1 2 , Jamie Rossjohn 1 2 8
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Victoria 3800, Australia
  2. ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, Victoria 3800, Australia
  3. Department of Immunology, University of Oslo and Oslo University Hospital- Rikshospitalet, Oslo, 0372, Norway
  4. Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo, Norway
  5. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  6. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  7. Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia
  8. Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom

Celiac disease (CeD) is a chronic inflammatory autoimmune-like condition characterised by disease-relevant HLA-DQ2.5/8 molecules that present gluten epitopes derived from wheat, rye and barley to reactive T cells. We investigated T cell responses towards immunodominant gluten epitopes; DQ2.5-glia-a1a (PFPQPELPY) and DQ2.5-glia-w1 (PFPQPEQPF) by examining patient T cell repertoire. It was found to be composed of highly specific and cross-reactive T cell clones (TCCs). We determined the ternary complex structures of cross-reactive TCR bound to HLA-DQ2.5-glia-a1 and HLA-DQ2.5-glia-w1 and epitope-specific TCR bound to HLA-DQ2.5-glia-w1 specific TCR. The interactions at the interface of TCR: peptide-HLA-DQ2.5 required for specificity provide an insight into how the TCRs distinguish between these highly similar peptides. Comparison of the TCR footprint contacts of the ternary complexes for both peptides revealed similar TCR docking with slight shift in docking angle. The hypervariable CDR3 loops were shown to be responsible for differential TCR recognition capacities of the cross-reactive versus discriminatory TCRs. We measured SPR binding affinities of the TCR-pHLA interaction, and found that the cross-reactive TCR is selectively promiscuous in binding as this TCR only bound these epitopes with similar affinity. This study highlights that cross-reactive T cells may also contribute to CeD pathogenesis. Furthermore, these cross-reactive and discriminatory T cells may prove to be important therapeutic targets in treatment of CeD.