Longitudinal Assessment of SARS-CoV-2-Specific T Cell Cytokine-Producing Responses for 1 Year Reveals Persistence of Multicytokine Proliferative Responses, with Greater Immunity Associated with Disease Severity

被引：21

作者：

Lin, Jonah ^{[1
]}

Law, Ryan ^{[1
]}

Korosec, Chapin S. ^{[6
]}

Zhou, Christine ^{[1
]}

Koh, Wan Hon ^{[1
,2
]}

Ghaemi, Mohammad Sajjad ^{[10
]}

Samaan, Philip ^{[2
,9
]}

Ooi, Hsu Kiang

Matveev, Vitaliy ^{[2
]}

Yue, FengYun ^{[2
]}

Gingras, Anne-Claude ^{[4
,12
]}

Estacio, Antonio ^{[5
]}

Buchholz, Megan ^{[8
]}

Cheatley, Patti Lou ^{[8
]}

Mohammadi, Avid ^{[2
]}

Kaul, Rupert ^{[2
]}

Pavinski, Katerina ^{[7
]}

Mubareka, Samira ^{[11
]}

McGeer, Allison J. ^{[4
]}

Leis, Jerome A. ^{[11
]}

Heffernan, Jane M. ^{[6
]}

Ostrowski, Mario ^{[1
,2
,3
,5
,9
]}

机构：

[1] Univ Toronto, Dept Immunol, Toronto, ON, Canada

[2] Univ Toronto, Dept Med, Toronto, ON, Canada

[3] Univ Toronto, Inst Med Sci, Toronto, ON, Canada

[4] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Sinai Hlth Syst, Toronto, ON, Canada

[5] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Unity Hlth, Toronto, ON, Canada

[6] York Univ, Dept Math & Stat, Modelling Infect & Immun Lab, Ctr Dis Modelling, Toronto, ON, Canada

[7] St Michaels Hosp, Dept Lab Med, Unity Hlth, Toronto, ON, Canada

[8] St Michaels Hosp, Kidney & Metab Program, Apheresis Unit, Unity Hlth, Toronto, ON, Canada

[9] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[10] Natl Res Council Canada, Digital Technol Res Ctr, Toronto, ON, Canada

[11] Sunnybrook Hlth Sci Ctr & Res Inst, Toronto, ON, Canada

[12] Univ Toronto, Dept Med Genet, Toronto, ON, Canada

来源：

JOURNAL OF VIROLOGY | 2022年 / 96卷 / 13期

基金：

加拿大自然科学与工程研究理事会;

关键词：

ELISpot assay; SARS-CoV-2; T cell immunity; cytokines; granzyme B; immune modeling; ACUTE RESPIRATORY SYNDROME; SARS CORONAVIRUS; B-CELL; EPITOPES; INFECTION; CAPACITY; CD4(+); GAMMA;

D O I：

10.1128/jvi.00509-22

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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-gamma), 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-gamma. Mathematical modeling predicted that (i) cytokine responses peaked at 6 days for IFN-gamma, 36 days for IL-2, and 7 days for GzmB, (ii) severe illness was associated with reduced IFN-gamma and GzmB but increased IL-2 production rates, and (iii) males displayed greater production of IFN-gamma, whereas females produced more GzmB. Ex vivo responses declined over time, with persistence of IL-2 in 86% and of IFN-gamma 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 (similar to 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.

引用

页数：24