SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors

The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8 + T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8 + T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here,...

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Published in:Nature communications Vol. 14; no. 1; pp. 6725 - 19
Main Authors: Choy, Cecily, Chen, Joseph, Li, Jiangyuan, Gallagher, D. Travis, Lu, Jian, Wu, Daichao, Zou, Ainslee, Hemani, Humza, Baptiste, Beverly A., Wichmann, Emily, Yang, Qian, Ciffelo, Jeffrey, Yin, Rui, McKelvy, Julia, Melvin, Denise, Wallace, Tonya, Dunn, Christopher, Nguyen, Cuong, Chia, Chee W., Fan, Jinshui, Ruffolo, Jeannie, Zukley, Linda, Shi, Guixin, Amano, Tomokazu, An, Yang, Meirelles, Osorio, Wu, Wells W., Chou, Chao-Kai, Shen, Rong-Fong, Willis, Richard A., Ko, Minoru S. H., Liu, Yu-Tsueng, De, Supriyo, Pierce, Brian G., Ferrucci, Luigi, Egan, Josephine, Mariuzza, Roy, Weng, Nan-Ping
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 23.10.2023
Nature Publishing Group
Nature Portfolio
Subjects:
13/1
13/106
13/31
38/39
38/91
631/250/2152/1566
631/326/596/4130
CD8 antigen
CD8-Positive T-Lymphocytes
Cell activation
Cell proliferation
Cell-mediated immunity
Chromatin
COVID-19
Epitopes
Epitopes, T-Lymphocyte
Expanders
Humanities and Social Sciences
Humans
Infections
Lymphocytes
Lymphocytes T
multidisciplinary
Nucleocapsid - metabolism
Nucleocapsids
Proteins
Receptors
Receptors, Antigen, T-Cell - metabolism
SARS-CoV-2 - metabolism
Science
Science (multidisciplinary)
Severe acute respiratory syndrome coronavirus 2
Spike Glycoprotein, Coronavirus
Spike protein
Stimulation
Structural analysis
T cell receptors
Transcriptomes
ISSN:2041-1723, 2041-1723
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Summary:The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8 + T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8 + T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8 + T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8 + T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8 + T cells and their proliferative response to stimulation did not decrease over one year. We identified the N 222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8 + T cells revealed highly restricted Vα gene usage (TRAV12-2) with limited CDR3α motifs, supported by structural characterization of the TCR–LLL–HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8 + T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8 + T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8 + T cell responses with a restricted TCR repertoire. Although SARS-CoV2 epitope characterization has been the focus of extensive research, these efforts have largely focused on the spike protein. Here, the authors demonstrate that CD8 + T cell responses can be directed against a dominant nucleocapsid epitope and rely on a highly focused T cell receptor repertoire.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-42430-z