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

Abstract

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 N222-230 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.

• Authors: Cecily Choy, Joseph Chen, Jiangyuan Li, D Travis Gallagher, Jian Lu, Daichao Wu, Ainslee Zou, Humza Hemani, Beverly A Baptiste, Emily Wichmann, Qian Yang, Jeffrey Ciffelo, Rui Yin, Julia McKelvy, Denise Melvin, Tonya Wallace, Christopher Dunn, Cuong Nguyen, Chee W Chia, Jinshui Fan, Jeannie Ruffolo, Linda Zukley, Guixin Shi, Tomokazu Amano, Yang An, Osorio Meirelles, Wells W Wu, Chao-Kai Chou, Rong-Fong Shen, Richard A Willis, Minoru S H Ko, Yu-Tsueng Liu, Supriyo De, Brian G Pierce, Luigi Ferrucci, Josephine Egan, Roy Mariuzza, Nan-Ping Weng
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 6725 (10 23 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37872153 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. Springer Nature Limited.

Chemical References

• Epitopes, T-Lymphocyte
• Receptors, Antigen, T-Cell
• Spike Glycoprotein, Coronavirus
• spike protein, SARS-CoV-2

Topics

• Humans
• CD8-Positive T-Lymphocytes
• COVID-19
• SARS-CoV-2 (metabolism)
• Epitopes, T-Lymphocyte
• Receptors, Antigen, T-Cell (metabolism)
• Nucleocapsid (metabolism)
• Spike Glycoprotein, Coronavirus