Poster Presentation Lorne Infection and Immunity 2013

Highly divergent T-cell receptor recognition modes to a bulged viral peptide bound to a human leukocyte antigen class I molecule (#136)

Yu-Chih Liu 1 , John J Miles 2 3 , Michelle A Neller 2 , Emma Gostick 3 , David A Price 3 , Anthony W Purcell 1 , James McCluskey 4 , Scott R Burrows 2 , Jamie Rossjohn 1 5 , Stephanie Gras 1
  1. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, , Monash University, Clayton, VIC, Australia
  2. Cellular immunology Laboratory, Queensland institute of medical research, Brisbane, Queensland, Australia
  3. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, Wales, UK
  4. Department of Microbiology and immunology, University of melbourne, Parkville, VIC, Australia
  5. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK
Although the Human leukocyte antigens (HLA) typically present short peptide antigens between 8-10 amino acids in length, longer epitopes (>10 amino acids) are frequently bound to HLA molecules and the mechanism by which TCRs utilise to engage these featured pHLA-I landscape remains unclear.Here, we compare the structures and functions of three distinct human TCRs, CA5, Sb27 and SB47, in response to a “super-bulged” viral epitope (LPEPLPQGQLTAY) presented by HLA-B*35:08. The CA5 and SB27 TCR interact with the HLA-B*3508-LPEP similarly, with the TCRs engaging directly above the central region of the peptide whilst making minimal contacts with HLA surface. Further, the differences in the CDR3b loops between the CA5 and SB27 had resulted in an altered antigen specificity profile towards the viral determinant. The SB47 TCR on the other hand, with a unique Va and Vb combination, approach the pHLA via a completely distinct mechanism. The SB47 TCR was positioned towards the extremely N-terminal end of the HLA-B35:08, therefore bypassing the bulged peptide landscape whilst making extensive contacts with the HLA surface. This docking footprint was more resemble to some autoreactive TCR-pMHC complexes, and provides the underlying basis of the markedly different pHLA specificity. Collectively, our result demonstrates the versatility of the human T-cell repertoire, in response to a structurally challenging pHLA target, and shapes our understanding towards the fine-specificity MHC restriction.
  1. Tynan, F. E., S. R. Burrows, A. M. Buckle, C. S. Clements, N. A. Borg, J. J. Miles, T. Beddoe, J. C. Whisstock, M. C. Wilce, S. L. Silins, J. M. Burrows, L. Kjer-Nielsen, L. Kostenko, A. W. Purcell, J. McCluskey and J. Rossjohn (2005) T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nat Immunol. 6, 1114-22.
  2. Tynan, F. E., H. H. Reid, L. Kjer-Nielsen, J. J. Miles, M. C. Wilce, L. Kostenko, N. A. Borg, N. A. Williamson, T. Beddoe, A. W. Purcell, S. R. Burrows, J. McCluskey and J. Rossjohn (2007) A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nat Immunol. 8, 268-76.
  3. Liu, Y. C., Z. Chen, S. R. Burrows, A. W. Purcell, J. McCluskey, J. Rossjohn and S. Gras The energetic basis underpinning T-cell receptor recognition of a super-bulged peptide bound to a major histocompatibility complex class I molecule. J Biol Chem. 287, 12267-76.