Poster Presentation 12th Australasian Virology Society Meeting 2024

First molecular insight into HLA-C contribution to COVID-19 outcome (#120)

You Min Ahn 1 2 , Yoshihiko Goto 3 , Janesha Maddumage 1 2 , Dimitra Chatzileontiadou 1 2 , Mako Toyoda 3 , Takeshi Nakama 3 , Huanyu Li 3 , Yoshiki Aritsu 3 , Takamasa Ueno 3 , Chihiro Motozono 3 , Stephanie Gras 1 2
  1. Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment (SABE), La Trobe University, Bundoora, Victoria 3086, Australia
  2. Infection and Immunity Program, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Bundoora, Victoria 3086, Australia
  3. Division of Infection and Immunity, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan

T cells are paramount to the adaptive immune system by controlling infection upon activation. The central interaction of cell-mediated adaptive immunity is between the ab T cell receptor (abTCR) and the presentation of an antigen bound by Human Leukocyte Antigen (HLA). As a crucial key event of the immune response, understanding the interaction between the TCR and peptide-HLA (pHLA) through structural biology, unravels the parameters that drive this interaction and its impact on the disease outcomes.

 

Our project aims to understand the link between effective antiviral T cell response in COVID-19 and the expression of HLA-C*12:02, as the role of HLA-C is highly understudied in controlling viral infections unlike HLA-A and HLA-B allomorphs. We have discovered a novel Nucleocapsid-derived peptide, capable of eliciting T cell responses in individuals expressing HLA-C*12:02.

 

We assessed the stability of the HLA in complex with the N-derived peptide by performing thermal stability assays. We then revealed the first crystal structure of the HLA-C*12:02 molecule presenting a SARS-CoV-2 peptide, giving the first insight into how T cells might engage with this HLA molecule. Furthermore, we also performed TCR repertoire analysis and revealed that clonotypic diversity underpins the response to this epitope and performed affinity measurement against HLA-C*12:02 molecule using surface plasmon resonance.

 

Our results represent the first study at the molecular level of HLA-C molecule associated with potent antiviral T cell responses, and how T cells engage with this HLA. This work will provide new avenues on how to better activate T cells.