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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Vydáno v:	Nature communications Ročník 14; číslo 1; s. 6725 - 19
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 23.10.2023 Nature Publishing Group Nature Portfolio
Témata:	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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-42430-z