Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

The length and biophysical properties of the peptide in the MHC groove predicts T cell receptor repertoire formation (#62)

John Miles 1 , Vanessa Venturi 2 , Stephanie Gras 3 , Jamie Rossjohn 3 , James McLaren 4 , Scott Burrows 1 , Melissa Bell 1 , Miles Davenport 5 , Adel Rahmani 6 , Daniel Douek 7 , David Price 4
  1. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  2. Computational Biology Group Centre for Vascular Research University of New South Wales, Sydney, NSW, Australia
  3. The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  4. Department of Infection, Immunity and Biochemistry, Henry Wellcome Building, Cardiff University School of Medicine, Cardiff, UK
  5. Complex Systems in Biology Group, Centre for Vascular Research, University of New South Wales, Kensington, NSW, Australia
  6. School of Mathematical Sciences University of Technology Sydney, Sydney, NSW, Australia
  7. Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA

The TCR repertoire mobilised against any given peptide (p) pMHC antigen can be either unpredictable (diverse) or predictable (biased). Likewise, the number of clonotypes mobilised against a pMHC antigen can swing considerably from one (monoclonal) to dozens (polyclonal). The mechanism behind this curious biological dichotomy has been a mystery for over 25 years. In an attempt to deconstruct the workings of this central immunological system we performed the largest epitope-specific TCR metastudy ever undertaken. Using a combination of published and newly generated TCRβ sequence data we built a database comprising 38,614 TCR TCRβ sequences across 570 samples for 76 HLA-restricted epitope-specific T cell responses. Multiparametric analysis revealed that the length of the peptide in the HLA groove could directly predict both the clonotype diversity and TCR gene make-up of an epitope-specific response. Additionally, by merging the TCR sequence database with a secondary database comprising 33 published and newly generated pHLA crystal structures we were able to directly link structural parameters with TCR repertoire formation. Specifically, we found that the number of bonds between the peptide and MHC was directly associated with the number of clonotypes mobilised. Additionally, we found that the surface complementarity score between the peptide and MHC was directly associated with the number of TRBV genes mobilised. This data brings us one step closer to predicting and manipulating the TCR repertoire for the purposes of rational vaccine design and therapeutic intervention.