ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Basis for the biased T cell response towards an immunodominant CD8+ T cell epitope from the SARS-CoV-2 spike protein (#277)

Priyanka Chaurasia 1 , Louise C. Rowntree 2 , Jennifer A. Juno 2 , Adam K. Wheatley 2 3 , Stephen K. Kent 2 3 , Katherine Kedzierska 2 , Jamie Rossjohn 1 4 5 , Jan Petersen 1 4
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University , Clayton, VIC, Australia
  2. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  3. Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Melbourne, VIC, Australia
  4. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia
  5. Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF, UK

CD8+ T cells play an important role in the immune response to SARS-CoV-2 infection and vaccination. Following the identification of several SARS-CoV-2 derived CD8+ T cell epitopes for several HLA class I alleles, recent studies have revealed surprisingly varied characteristics of associated CD8+ T cell responses. The molecular basis for CD8+ T cell recognition of SARS-CoV-2 derived epitopes which ultimately determines the Repertoire diversity and quality of T cell responses remains unclear. Following SARS-CoV-2 infection or vaccination the SARS-CoV-2 derived S269-277 peptide elicits a dominant CD8+ T cell response in carriers of the common HLA-A2 allele. Since HLA-A2S269-277-specific CD8+ T cells utilise a biased TRAV12 gene usage, we sought to understand the molecular basis for this TRAV12 dominance. We expressed and refolded four TRAV12+ TCRs which bound the HLA-A2S269-277 complex high affinity. We determined the crystal structure of the HLA-A2S269-277 binary complex and subsequently the ternary structure of a TRAV12+ TCR bound to HLA-A2S269-277. The TRAV12+ TCR docked atop HLA-A2 with standard docking polarity, whereupon HLA-A2S269-277 recognition was dominated by both TRAV12 germline-encoded residues and residues from conserved sequence motifs located within the CDR3a and CDR3b loops. Here, the TCR made extensive contacts along the entire length of the S269-277 peptide, suggesting that the TRAV12+TCRs would be sensitive to any sequence variation within this epitope. To examine this, we investigated cross-reactivity towards analogous peptides from existing SARS-CoV-2 variants and closely related coronaviruses. We show, via surface plasmon resonance and tetramer studies, that the TRAV12+ T cell repertoire cross-reacts poorly with these analogous epitopes. Overall, we defined the structural basis underpinning biased TCR recognition of CD8+ T cells directed at an immunodominant HLA-A2S269-277 epitope and provide a framework for understanding TCR cross-reactivity towards viral variants within S269-277 peptide.