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

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 and Nan-Ping Weng ()
Additional contact information
Cecily Choy: National Institute on Aging, NIH
Joseph Chen: National Institute on Aging, NIH
Jiangyuan Li: National Institute on Aging, NIH
D. Travis Gallagher: National Institute of Standards and Technology (NIST)
Jian Lu: National Institute on Aging, NIH
Daichao Wu: University of Maryland Institute for Bioscience and Biotechnology Research
Ainslee Zou: National Institute on Aging, NIH
Humza Hemani: National Institute on Aging, NIH
Beverly A. Baptiste: National Institute on Aging, NIH
Emily Wichmann: National Institute on Aging, NIH
Qian Yang: National Institute on Aging, NIH
Jeffrey Ciffelo: National Institute on Aging, NIH
Rui Yin: University of Maryland Institute for Bioscience and Biotechnology Research
Julia McKelvy: National Institute on Aging, NIH
Denise Melvin: National Institute on Aging, NIH
Tonya Wallace: National Institute on Aging, NIH
Christopher Dunn: National Institute on Aging, NIH
Cuong Nguyen: National Institute on Aging, NIH
Chee W. Chia: National Institute on Aging, NIH
Jinshui Fan: National Institute on Aging, NIH
Jeannie Ruffolo: National Institute on Aging, NIH
Linda Zukley: National Institute on Aging, NIH
Guixin Shi: Diagnologix LLC
Tomokazu Amano: Elixirgen Therapeutics, Inc
Yang An: National Institute on Aging, NIH
Osorio Meirelles: National Institute on Aging, NIH
Wells W. Wu: Facility for Biotechnology Resources, CBER, Food and Drug Administration
Chao-Kai Chou: Facility for Biotechnology Resources, CBER, Food and Drug Administration
Rong-Fong Shen: Facility for Biotechnology Resources, CBER, Food and Drug Administration
Richard A. Willis: NIH Tetramer Core Facility at Emory University
Minoru S. H. Ko: Elixirgen Therapeutics, Inc
Yu-Tsueng Liu: Diagnologix LLC
Supriyo De: National Institute on Aging, NIH
Brian G. Pierce: University of Maryland Institute for Bioscience and Biotechnology Research
Luigi Ferrucci: National Institute on Aging, NIH
Josephine Egan: National Institute on Aging, NIH
Roy Mariuzza: University of Maryland Institute for Bioscience and Biotechnology Research
Nan-Ping Weng: National Institute on Aging, NIH

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42430-z

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