Parallel detection of SARS-CoV-2 epitopes reveals dynamic immunodominance profiles of CD8+ T memory cells in convalescent COVID-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 Jm Verstegen; S Marieke van Ham; Wim Je van Esch; Klaas Pjm van Gisbergen; Pleun Hombrink; Anja Ten Brinke; Carolien E van de Sandt

doi:10.1002/cti2.1423

Parallel detection of SARS-CoV-2 epitopes reveals dynamic immunodominance profiles of CD8⁺ T memory cells in convalescent COVID-19 donors

Clin Transl Immunology. 2022 Oct 14;11(10):e1423. doi: 10.1002/cti2.1423. eCollection 2022.

Authors

Jet van den Dijssel^{1

2

3}, Ruth R Hagen^{1

2

3}, Rivka de Jongh^{2

4}, Maurice Steenhuis^{2

4}, Theo Rispens^{2

4}, Dionne M Geerdes⁵, Juk Yee Mok⁵, Angela Hm Kragten⁵, Mariël C Duurland^{2

4}, Niels Jm Verstegen^{2

4}, S Marieke van Ham^{2

4

6}, Wim Je van Esch⁵, Klaas Pjm van Gisbergen^{1

2}, Pleun Hombrink^{1

2}, Anja Ten Brinke^{2

4}, Carolien E van de Sandt^{1

2

7}

Affiliations

¹ Department of Hematopoiesis Sanquin Research Amsterdam The Netherlands.
² Landsteiner Laboratory Amsterdam UMC location University of Amsterdam Amsterdam The Netherlands.
³ Department of Experimental Immunohematology Sanquin Research Amsterdam The Netherlands.
⁴ Department of Immunopathology Sanquin Research Amsterdam The Netherlands.
⁵ Sanquin Reagents B.V. Amsterdam The Netherlands.
⁶ Swammerdam Institute for Life Sciences University of Amsterdam Amsterdam The Netherlands.
⁷ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity University of Melbourne Melbourne VIC Australia.

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.

Keywords: CD8+ T cells; SARS‐CoV‐2; convalescence; epitopes; immunodominance; infection.