SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses

Benedikt Agerer; Maximilian Koblischke; Venugopal Gudipati; Luis Fernando Montaño-Gutierrez; Mark Smyth; Alexandra Popa; Jakob-Wendelin Genger; Lukas Endler; David M Florian; Vanessa Mühlgrabner; Marianne Graninger; Stephan W Aberle; Anna-Maria Husa; Lisa Ellen Shaw; Alexander Lercher; Pia Gattinger; Ricard Torralba-Gombau; Doris Trapin; Thomas Penz; Daniele Barreca; Ingrid Fae; Sabine Wenda; Marianna Traugott; Gernot Walder; Winfried F Pickl; Volker Thiel; Franz Allerberger; Hannes Stockinger; Elisabeth Puchhammer-Stöckl; Wolfgang Weninger; Gottfried Fischer; Wolfgang Hoepler; Erich Pawelka; Alexander Zoufaly; Rudolf Valenta; Christoph Bock; Wolfgang Paster; René Geyeregger; Matthias Farlik; Florian Halbritter; Johannes B Huppa; Judith H Aberle; Andreas Bergthaler

doi:10.1126/SCIIMMUNOL.ABG6461

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses

Benedikt Agerer
, Maximilian Koblischke
, Venugopal Gudipati
, Luis Fernando Montaño-Gutierrez
, Mark Smyth
, Alexandra Popa
, Jakob-Wendelin Genger
, Lukas Endler
, David M Florian
, Vanessa Mühlgrabner
, Marianne Graninger
, Stephan W Aberle
, Anna-Maria Husa
, Lisa Ellen Shaw
, Alexander Lercher
, Pia Gattinger
, Ricard Torralba-Gombau
, Doris Trapin
, Thomas Penz
, Daniele Barreca

Ingrid Fae, Sabine Wenda, Marianna Traugott, Gernot Walder, Winfried F Pickl, Volker Thiel, Franz Allerberger, Hannes Stockinger, Elisabeth Puchhammer-Stöckl, Wolfgang Weninger, Gottfried Fischer, Wolfgang Hoepler, Erich Pawelka, Alexander Zoufaly, Rudolf Valenta, Christoph Bock, Wolfgang Paster, René Geyeregger, Matthias Farlik, Florian Halbritter, Johannes B Huppa, Judith H Aberle, Andreas Bergthaler

Scientific Working Group Allergology and Immunology

Research output: Journal article (peer-reviewed) › Journal article

141 Citations (Scopus)

Abstract

CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.

Original language	English
Article number	abg6461
Journal	Science immunology
Volume	6
Issue number	57
DOIs	https://doi.org/10.1126/SCIIMMUNOL.ABG6461
Publication status	Published - 25 Mar 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CD8-Positive T-Lymphocytes/immunology
COVID-19/genetics
Cell Proliferation
Epitopes, T-Lymphocyte/genetics
HLA-A Antigens/immunology
High-Throughput Nucleotide Sequencing
Humans
Immunity, Cellular
Interferon-gamma/immunology
Mutation
Peptides/genetics
SARS-CoV-2/genetics

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10.1126/SCIIMMUNOL.ABG6461

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Agerer, B., Koblischke, M., Gudipati, V., Montaño-Gutierrez, L. F., Smyth, M., Popa, A., Genger, J.-W., Endler, L., Florian, D. M., Mühlgrabner, V., Graninger, M., Aberle, S. W., Husa, A.-M., Shaw, L. E., Lercher, A., Gattinger, P., Torralba-Gombau, R., Trapin, D., Penz, T., ... Bergthaler, A. (2021). SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses. Science immunology, 6(57), Article abg6461. https://doi.org/10.1126/SCIIMMUNOL.ABG6461

@article{b98bdc663eb74e449f97e0e1e22a7e47,

title = "SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses",

abstract = "CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.",

keywords = "CD8-Positive T-Lymphocytes/immunology, COVID-19/genetics, Cell Proliferation, Epitopes, T-Lymphocyte/genetics, HLA-A Antigens/immunology, High-Throughput Nucleotide Sequencing, Humans, Immunity, Cellular, Interferon-gamma/immunology, Mutation, Peptides/genetics, SARS-CoV-2/genetics",

author = "Benedikt Agerer and Maximilian Koblischke and Venugopal Gudipati and Monta{\~n}o-Gutierrez, \{Luis Fernando\} and Mark Smyth and Alexandra Popa and Jakob-Wendelin Genger and Lukas Endler and Florian, \{David M\} and Vanessa M{\"u}hlgrabner and Marianne Graninger and Aberle, \{Stephan W\} and Anna-Maria Husa and Shaw, \{Lisa Ellen\} and Alexander Lercher and Pia Gattinger and Ricard Torralba-Gombau and Doris Trapin and Thomas Penz and Daniele Barreca and Ingrid Fae and Sabine Wenda and Marianna Traugott and Gernot Walder and Pickl, \{Winfried F\} and Volker Thiel and Franz Allerberger and Hannes Stockinger and Elisabeth Puchhammer-St{\"o}ckl and Wolfgang Weninger and Gottfried Fischer and Wolfgang Hoepler and Erich Pawelka and Alexander Zoufaly and Rudolf Valenta and Christoph Bock and Wolfgang Paster and Ren{\'e} Geyeregger and Matthias Farlik and Florian Halbritter and Huppa, \{Johannes B\} and Aberle, \{Judith H\} and Andreas Bergthaler",

year = "2021",

month = mar,

day = "25",

doi = "10.1126/SCIIMMUNOL.ABG6461",

language = "English",

volume = "6",

journal = "Science immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "57",

}

Agerer, B, Koblischke, M, Gudipati, V, Montaño-Gutierrez, LF, Smyth, M, Popa, A, Genger, J-W, Endler, L, Florian, DM, Mühlgrabner, V, Graninger, M, Aberle, SW, Husa, A-M, Shaw, LE, Lercher, A, Gattinger, P, Torralba-Gombau, R, Trapin, D, Penz, T, Barreca, D, Fae, I, Wenda, S, Traugott, M, Walder, G, Pickl, WF, Thiel, V, Allerberger, F, Stockinger, H, Puchhammer-Stöckl, E, Weninger, W, Fischer, G, Hoepler, W, Pawelka, E, Zoufaly, A, Valenta, R, Bock, C, Paster, W, Geyeregger, R, Farlik, M, Halbritter, F, Huppa, JB, Aberle, JH & Bergthaler, A 2021, 'SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses', Science immunology, vol. 6, no. 57, abg6461. https://doi.org/10.1126/SCIIMMUNOL.ABG6461

TY - JOUR

T1 - SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses

AU - Agerer, Benedikt

AU - Koblischke, Maximilian

AU - Gudipati, Venugopal

AU - Montaño-Gutierrez, Luis Fernando

AU - Smyth, Mark

AU - Popa, Alexandra

AU - Genger, Jakob-Wendelin

AU - Endler, Lukas

AU - Florian, David M

AU - Mühlgrabner, Vanessa

AU - Graninger, Marianne

AU - Aberle, Stephan W

AU - Husa, Anna-Maria

AU - Shaw, Lisa Ellen

AU - Lercher, Alexander

AU - Gattinger, Pia

AU - Torralba-Gombau, Ricard

AU - Trapin, Doris

AU - Penz, Thomas

AU - Barreca, Daniele

AU - Fae, Ingrid

AU - Wenda, Sabine

AU - Traugott, Marianna

AU - Walder, Gernot

AU - Pickl, Winfried F

AU - Thiel, Volker

AU - Allerberger, Franz

AU - Stockinger, Hannes

AU - Puchhammer-Stöckl, Elisabeth

AU - Weninger, Wolfgang

AU - Fischer, Gottfried

AU - Hoepler, Wolfgang

AU - Pawelka, Erich

AU - Zoufaly, Alexander

AU - Valenta, Rudolf

AU - Bock, Christoph

AU - Paster, Wolfgang

AU - Geyeregger, René

AU - Farlik, Matthias

AU - Halbritter, Florian

AU - Huppa, Johannes B

AU - Aberle, Judith H

AU - Bergthaler, Andreas

PY - 2021/3/25

Y1 - 2021/3/25

N2 - CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.

AB - CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.

KW - CD8-Positive T-Lymphocytes/immunology

KW - COVID-19/genetics

KW - Cell Proliferation

KW - Epitopes, T-Lymphocyte/genetics

KW - HLA-A Antigens/immunology

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Immunity, Cellular

KW - Interferon-gamma/immunology

KW - Mutation

KW - Peptides/genetics

KW - SARS-CoV-2/genetics

UR - https://www.scopus.com/pages/publications/85102706961

U2 - 10.1126/SCIIMMUNOL.ABG6461

DO - 10.1126/SCIIMMUNOL.ABG6461

M3 - Journal article

C2 - 33664060

SN - 2470-9468

VL - 6

JO - Science immunology

JF - Science immunology

IS - 57

M1 - abg6461

ER -

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8+ T cell responses

Abstract

UN SDGs

Keywords

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