Poster Presentation Lorne Infection and Immunity 2020

Reverse T Cell Receptor Docking on a Major Histocompatibility Class I Complex limits efficient signal transduction  (#189)

Carine Farenc 1 , P Zareie 1 , C Szeto 1 , A Nguyen 1 , A J Fulcher 2 , L Wojciech 3 , Q Wei 3 , N R J Gascoigne 3 4 , J Petersen 1 , S Gras 1 , J Rossjohn 1 , N L La Grunta 1
  1. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. Monash Micro Imaging, Monash University, Clayton, VIC, Australia
  3. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  4. Immunology Program, Life Sciences Institute, National University of Singapore; NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, SIngapore, Singapore

T cells are essential to adaptive immunity and are characterized by expression of a T-cell receptor (TCR) on the cell surface. The generation of the TCR theoretically allows a diversity of more than 1015 different TCRs, of which 107 can be found within any individual. The differentiation of naïve T cells into mature T cells is triggered by antigen encounter, however the process of recruitment of T-cells from the naïve repertoire into the immune repertoire remains poorly understood.

Using an influenza virus infection model, we studied the CD8+ T cell response directed to an immunodominant peptide epitope (NP366) presented by MHC molecule H-2Db and analyzed the TCR usage in both the naïve and immune repertoire. The results showed that 25% of the naive repertoire was represented by the TRBV17+ T cell population but that this preference is not conserved in the immune repertoire (<1%). In order to understand the process of recruitment, we solved the structures of two TRBV17+ TCRs from the naïve T cell repertoire in complex with their pMHC ligand and biophysically characterized the interaction. Surprisingly, those two structures presented a 180 degrees reversed polarity compared to the conventional TCR-pMHC-I docking.

Our work suggests that in order to have efficient signal transduction, the TCR needs to bind to the pMHC in a precise orientation defined by the structural constrains of the signaling machinery.