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Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype.
Proc Natl Acad Sci U S A. 2020 09 29; 117(39):24384-24391.PN

Abstract

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.

Links

Publisher Full Text
ncbi.nlm.nih.gov
pnas.org
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Authors+Show Affiliations

Habel JR
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Nguyen THO
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
van de Sandt CE
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia. Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, 1066 CX Amsterdam, Netherlands.
Juno JA
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Chaurasia P
Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Wragg K
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Koutsakos M
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Hensen L
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Jia X
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Chua B
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Zhang W
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Tan HX
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Flanagan KL
Department of Infectious Diseases, Launceston General Hospital, Launceston, TAS 7250, Australia. School of Health Sciences and School of Medicine, University of Tasmania, Launceston, TAS 7248, Australia. Department of Immunology and Pathology, Monash University, Melbourne, VIC 3800, Australia. School of Health and Biomedical Science, Royal Melbourne Institute of Technology University, Melbourne, VIC 3000, Australia.
Doolan DL
Centre for Molecular Therapeutics, Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, QLD 4814, Australia.
Torresi J
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Chen W
Department of Biochemistry and Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora 3084 VIC, Australia.
Wakim LM
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Cheng AC
School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia. Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC 3004, Australia.
Doherty PC
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia; pcd@unimelb.edu.au kkedz@unimelb.edu.au. Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Petersen J
Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton 3800, VIC, Australia.
Rossjohn J
Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton 3800, VIC, Australia. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
Wheatley AK
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia. Ausralian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC 3010, Australia.
Kent SJ
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia. Ausralian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC 3010, Australia.
Rowntree LC
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
Kedzierska K
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia; pcd@unimelb.edu.au kkedz@unimelb.edu.au.

MeSH

BetacoronavirusCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCOVID-19Coronavirus InfectionsEpitopes, T-LymphocyteFemaleHLA-A2 AntigenHumansImmunologic MemoryImmunophenotypingLeukocytes, MononuclearLymphocyte ActivationMaleMiddle AgedPandemicsPeptide FragmentsPneumonia, ViralPolyproteinsSARS-CoV-2Spike Glycoprotein, CoronavirusViral Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32913053

Citation

Habel, Jennifer R., et al. "Suboptimal SARS-CoV-2-specific CD8+ T Cell Response Associated With the Prominent HLA-A*02:01 Phenotype." Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 39, 2020, pp. 24384-24391.
Habel JR, Nguyen THO, van de Sandt CE, et al. Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype. Proc Natl Acad Sci U S A. 2020;117(39):24384-24391.
Habel, J. R., Nguyen, T. H. O., van de Sandt, C. E., Juno, J. A., Chaurasia, P., Wragg, K., Koutsakos, M., Hensen, L., Jia, X., Chua, B., Zhang, W., Tan, H. X., Flanagan, K. L., Doolan, D. L., Torresi, J., Chen, W., Wakim, L. M., Cheng, A. C., Doherty, P. C., ... Kedzierska, K. (2020). Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype. Proceedings of the National Academy of Sciences of the United States of America, 117(39), 24384-24391. https://doi.org/10.1073/pnas.2015486117
Habel JR, et al. Suboptimal SARS-CoV-2-specific CD8+ T Cell Response Associated With the Prominent HLA-A*02:01 Phenotype. Proc Natl Acad Sci U S A. 2020 09 29;117(39):24384-24391. PubMed PMID: 32913053.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype. AU - Habel,Jennifer R, AU - Nguyen,Thi H O, AU - van de Sandt,Carolien E, AU - Juno,Jennifer A, AU - Chaurasia,Priyanka, AU - Wragg,Kathleen, AU - Koutsakos,Marios, AU - Hensen,Luca, AU - Jia,Xiaoxiao, AU - Chua,Brendon, AU - Zhang,Wuji, AU - Tan,Hyon-Xhi, AU - Flanagan,Katie L, AU - Doolan,Denise L, AU - Torresi,Joseph, AU - Chen,Weisan, AU - Wakim,Linda M, AU - Cheng,Allen C, AU - Doherty,Peter C, AU - Petersen,Jan, AU - Rossjohn,Jamie, AU - Wheatley,Adam K, AU - Kent,Stephen J, AU - Rowntree,Louise C, AU - Kedzierska,Katherine, Y1 - 2020/09/10/ PY - 2020/9/12/pubmed PY - 2020/10/21/medline PY - 2020/9/11/entrez KW - CD8+ T cells KW - COVID-19 KW - HLA-A*02:01 KW - SARS-CoV-2 epitopes SP - 24384 EP - 24391 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 117 IS - 39 N2 - An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/32913053/Suboptimal_SARS_CoV_2_specific_CD8+_T_cell_response_associated_with_the_prominent_HLA_A_02:01_phenotype_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=32913053 DB - PRIME DP - Unbound Medicine ER -