MI2025 – Celine Chua

Title:
Reactivation of cross-reactive T cells by SARS-CoV-2 mRNA vaccination

Abstract:
Cross-reactivity is a phenomenon in which T cells recognise and respond to new antigens that are structurally similar, but not identical to the original target antigen they were originally primed against. In the context of SARS-CoV-2, the presence of pre-existing, cross-reactive T cells has been widely reported in individuals with no prior exposure to the virus, highlighting ubiquitous pre-existing T cell memory attributed to previous exposure to common cold coronaviruses. The protection afforded by cross-reactivity against new, emerging antigens remains a topic of contentious debate, and is influenced by variables such as T cell avidity – defined as the overall sensitivity to its cognate antigen. High avidity T cells are highly responsive to antigens and therefore are theorised to exhibit higher functionality for enhanced viral protection. In contrast, low avidity T cells do not undergo robust activation, and hence could possess lacklustre effector capabilities that impedes optimal responses by occupying the immunological synapse. Whether pre-existing, cross-reactive T cells could be reactivated by SARS-CoV-2 and the immunological outcomes following reactivation remains obscure.

Here, we profiled the dynamics of cross-reactive CD4+ T cell responses in a longitudinal cohort following SARS-CoV-2 mRNA vaccination by analysing HCoV-229E-specific CD4 T cells. Peripheral blood mononuclear cells (PBMCs) collected at baseline, 2 weeks post-primary dose, 2 weeks post-second dose, and 6 months post-second dose were stimulated with whole spike proteins of SARS-CoV-2 (CoV2) and HCoV-229E (229E). Pre-existing CoV-2-reactive T cells were observed before vaccination in most individuals. mRNA vaccination induced robust expansion of CoV2-specific and 229E-specific CD4 T cells. Surprisingly, frequencies of high avidity 229e-specific, but not low avidity 229e-specific, CD4 T cells expanded after two doses of vaccination. High avidity CoV-2- and 229E-specific T cells shared similar features and were dominated by Th1 and Tfh phenotypes. By contrast, low-avidity T cells showed enrichment for inflammatory profiles. All in all, this study provides novel insights on the protective role of cross-reactive T cells.

Biography:
Celine is a first-year doctoral student at the Department of Immunology, Graduate School of Medicine, Kyoto University. She received her B.Sc (Hons) in Life Sciences from the National University of Singapore and M.Sc in Medical Science from Kyoto University. Her current research focuses on the characterisation of antigen-specific T cells during infection and vaccination.