Abstract
Cell-mediated immunity is critical for long-term protection against most viral infections, including coronaviruses. We studied 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected survivors over a 1-year post-symptom onset (PSO) interval by ex vivo cytokine enzyme-linked immunosorbent spot assay (ELISpot) assay. All subjects demonstrated SARS-CoV-2-specific gamma interferon (IFN-γ), interleukin 2 (IL-2), and granzyme B (GzmB) T cell responses at presentation, with greater frequencies in severe disease. Cytokines, mainly produced by CD4 + T cells, targeted all structural proteins (nucleocapsid, membrane, and spike) except envelope, with GzmB and IL-2 greater than IFN-γ. Mathematical modeling predicted that (i) cytokine responses peaked at 6 days for IFN-γ, 36 days for IL-2, and 7 days for GzmB, (ii) severe illness was associated with reduced IFN-γ and GzmB but increased IL-2 production rates, and (iii) males displayed greater production of IFN-γ, whereas females produced more GzmB. Ex vivo responses declined over time, with persistence of IL-2 in 86% and of IFN-γ and GzmB in 70% of subjects at a median of 336 days PSO. The average half-life of SARS-CoV-2-specific cytokine-producing cells was modeled to be 139 days (~4.6 months). Potent T cell proliferative responses persisted throughout observation, were CD4 dominant, and were capable of producing all 3 cytokines. Several immunodominant CD4 and CD8 epitopes identified in this study were shared by seasonal coronaviruses or SARS-CoV-1 in the nucleocapsid and membrane regions. Both SARS-CoV-2-specific CD4 + and CD8 + T cell clones were able to kill target cells, though CD8 tended to be more potent. IMPORTANCE Our findings highlight the relative importance of SARS-CoV-2-specific GzmB-producing T cell responses in SARS-CoV-2 control and shared CD4 and CD8 immunodominant epitopes in seasonal coronaviruses or SARS-CoV-1, and they indicate robust persistence of T cell memory at least 1 year after infection. Our findings should inform future strategies to induce T cell vaccines against SARS-CoV-2 and other coronaviruses.
Keywords: ELISpot assay; SARS-CoV-2; T cell immunity; cytokines; granzyme B; immune modeling.
【저자키워드】 SARS-CoV-2, Cytokines, T cell immunity, ELISpot assay, granzyme B, immune modeling., 【초록키워드】 Coronaviruses, Vaccine, coronavirus, Cytokines, Immunity, T cells, Infection, interferon, cytokine, severe acute respiratory syndrome Coronavirus, CD4, CD8, SARS-CoV-1, viral infections, immune, Epitopes, T cell, interleukin, nucleocapsid, persistence, response, T cell responses, male, female, envelope, membrane, structural proteins, GzmB, ELISPOT, structural protein, seasonal coronaviruses, epitope, Critical, ELISpot assay, potent, T cell response, immunodominant epitopes, Cell-mediated immunity, IFN-γ, IL-2, Frequency, granzyme B, cytokine response, severe disease, PSO, target cells, gamma interferon, observation, Ex vivo, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, subject, other coronaviruses, all subjects, post-symptom onset, average, clone, T cell memory, survivor, immunodominant, interleukin 2, dominant, regions, immunodominant epitope, Cell, enzyme-linked immunosorbent, highlight, robust, greater, produced, predicted, peaked, reduced, median, demonstrated, induce, producing, proliferative, kill, declined, seasonal coronavirus, 【제목키워드】 response, assessment, longitudinal, Year,