Parallel detection of <scp>SARS‐CoV</scp>‐2 epitopes reveals dynamic immunodominance profiles of <scp>CD8</scp><sup>+</sup> T memory cells in convalescent <scp>COVID</scp>‐19 donors
Jet van den Dijssel, Ruth R. Hagen, Rivka de Jongh, Maurice Steenhuis, Theo Rispens, Dionne M. Geerdes, Juk Yee Mok, Angela HM. Kragten, Mariël C Duurland, Niels J. M. Verstegen, S. Marieke van Ham, Wim JE. van Esch, Klaas P. J. M. van Gisbergen, Pleun Hombrink, Anja ten Brinke, Carolien E. van de Sandt
Abstract
Abstract Objectives High‐magnitude CD8 + T cell responses are associated with mild COVID‐19 disease; however, the underlying characteristics that define CD8 + T cell‐mediated protection are not well understood. The antigenic breadth and the immunodominance hierarchies of epitope‐specific CD8 + T cells remain largely unexplored and are essential for the development of next‐generation broad‐protective vaccines. This study identified a broad spectrum of conserved SARS‐CoV‐2 CD8 + T cell epitopes and defined their respective immunodominance and phenotypic profiles following SARS‐CoV‐2 infection. Methods CD8 + T cells from 51 convalescent COVID‐19 donors were analysed for their ability to recognise 133 predicted and previously described SARS‐CoV‐2‐derived peptides restricted by 11 common HLA class I allotypes using heterotetramer combinatorial coding, which combined with phenotypic markers allowed in‐depth ex vivo profiling of CD8 + T cell responses at quantitative and phenotypic levels. Results A comprehensive panel of 49 mostly conserved SARS‐CoV‐2‐specific CD8 + T cell epitopes, including five newly identified low‐magnitude epitopes, was established. We confirmed the immunodominance of HLA‐A*01:01/ORF1ab 1637–1646 and B*07:02/N 105–113 and identified B*35:01/N 325–333 as a third epitope with immunodominant features. The magnitude of subdominant epitope responses, including A*03:01/N 361–369 and A*02:01/S 269–277 , depended on the donors' HLA‐I context. All epitopes expressed prevalent memory phenotypes, with the highest memory frequencies in severe COVID‐19 donors. Conclusion SARS‐CoV‐2 infection induces a predominant CD8 + T memory response directed against a broad spectrum of conserved SARS‐CoV‐2 epitopes, which likely contributes to long‐term protection against severe disease. The observed immunodominance hierarchy emphasises the importance of T cell epitopes derived from nonspike proteins to the overall protective and cross‐reactive immune response, which could aid future vaccine strategies.