SARS-CoV-2 infection establishes an enhanced, stable, and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using highly restricted TCRs

Published

October 23, 2023

Author(s)

Cecily Choy, Joseph Chen, Jiangyuan Li, Jian Lu, Daichao Wu, Ainslee Zou, Humza Hemani, Beverly Baptiste, Emily Wichmann, Qian Yang, Jeffrey Ciffelo, Rui Yin, Julia McKelvy, Denise Melvin, Tonya Wallace, Christopher Dunn, Cuong Nguyen, Chee Chia, Jingshui Fan, Jeannie Ruffolo, Linda Zukley, Guixin Shi, Tomokazu Amano, An Yang, Osorio Meirelles, Wells Wu, Rong-Fong Chen, RICHARD WILLIS, Minoru Ko, Y-T Liu, Supriyo De, Brian Pierce, Luigi Ferrucci, josephine egan, Roy Mariuzza, Nan-ping Weng, David Travis Gallagher

Abstract

We analyzed circulating CD8+ T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein in HLA-A2+ unexposed and recovered COVID-19 patients using multi-color flow cytometry and scRNAseq. We found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8+ T cells but significantly enhanced activation-induced proliferation. In contrast to a decline in IgG titer against the N protein over time, the frequencies of N-recognizing CD8+ T cells and their response to stimulation did not appear to decrease over one year. In vitro antigenic challenge identified N222-230 (LLLDRLNQL referred to as LLL) as a dominant epitope that elicited the greatest response (number of responders and magnitude of expansion) from both convalescent and uninfected donors. Analysis of scTCRseq of LLL-specific CD8+ T cells using scTCRseq revealed highly restricted Vgene usage (TRAV12-2) with limited CDR3 motifs, which was supported by structural characterization of a TCR–LLL–HLA-A2 complex. Lastly, transcriptome analysis of CD8+ T cells between expanders and non-expanders identified increased gene expressions associated with differentiation of CD8+ T cells from non- expanders which are shared across the different subsets in a TCR-independent manner. These results show that SARS-CoV-2 infection resulted in significantly enhanced proliferation of LLL-specific CD8+ T cells and suggest that an altered transcriptome is the underlying mechanism controlling activation-induced expansion of LLL-specific CD8+ T cells.

Citation

Nature Communications

Volume

14

Issue

1

Pub Type

Journals

Download Paper

https://doi.org/10.1038/s41467-023-42430-z

Local Download

Keywords

Covid-19, immunity, patient, protein structure, MHC

Citation

Choy, C. , Chen, J. , Li, J. , Lu, J. , Wu, D. , Zou, A. , Hemani, H. , Baptiste, B. , Wichmann, E. , Yang, Q. , Ciffelo, J. , Yin, R. , McKelvy, J. , Melvin, D. , Wallace, T. , Dunn, C. , Nguyen, C. , Chia, C. , Fan, J. , Ruffolo, J. , Zukley, L. , Shi, G. , Amano, T. , Yang, A. , Meirelles, O. , Wu, W. , Chen, R. , WILLIS, R. , Ko, M. , Liu, Y. , De, S. , Pierce, B. , Ferrucci, L. , egan, J. , Mariuzza, R. , Weng, N. and Gallagher, D. (2023), SARS-CoV-2 infection establishes an enhanced, stable, and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using highly restricted TCRs, Nature Communications, [online], https://doi.org/10.1038/s41467-023-42430-z, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=936478 (Accessed June 28, 2025)