tetano
Editor, Senior Moderator
Front Immunol
. 2025 Oct 2:16:1576903.
doi: 10.3389/fimmu.2025.1576903. eCollection 2025. Patterns of restricted TCR usage following SARS-CoV-2 vaccination and severe disease
Emily Parsons[SUP] 1 [/SUP], Zhongyan Lu[SUP] 1 2 [/SUP], Stephanie A Richard[SUP] 2 3 [/SUP], Amanda Zelkoski[SUP] 1 2 [/SUP], Janifer Le[SUP] 1 2 [/SUP], Naraen Palanikumar[SUP] 1 2 [/SUP], Phuong Nguyen[SUP] 1 2 [/SUP], Camille Alba[SUP] 2 4 5 [/SUP], Gauthaman Sukumar[SUP] 2 4 5 [/SUP], John Rosenberger[SUP] 2 4 [/SUP], Xijun Zhang[SUP] 2 4 [/SUP], Timothy H Burgess[SUP] 3 [/SUP], Rhonda Colombo[SUP] 2 3 6 7 [/SUP], Katrin Mende[SUP] 2 3 8 [/SUP], Catherine Berjohn[SUP] 2 6 9 [/SUP], Nursat Epsi[SUP] 2 3 [/SUP], Brian K Agan[SUP] 2 3 [/SUP], David Tribble[SUP] 3 [/SUP], David A Lindholm[SUP] 6 8 [/SUP], Clifton L Dalgard[SUP] 4 5 [/SUP], Simon D Pollett[SUP] 2 3 [/SUP], Allison M W Malloy[SUP] 1 [/SUP]; EPICC COVID-19 Cohort Study Group
Affiliations
Introduction: T cells influence COVID-19 severity and establish long-lasting immune memory in response to vaccination and infection. The diversity of the T cell repertoire, and complexity of T cell epitope recognition, make it challenging to define protective epitope-specific T cells. In this study, we created a highly specific TCR meta-database to identify T cell epitopes from the nearly complete SARS-CoV-2 proteome and determine whether vaccination with mRNA vaccines influenced the TCR repertoire.
Methods: Using this meta-database, we analyzed immunosequencing data of genomic DNA to define the variable region of T cell receptor (TCR) b chain (TCRB) sequences among participants in a longitudinal COVID-19 cohort study. The TCR repertoire was compared between participants who were vaccinated or unvaccinated against SARS-CoV-2 and stratified by disease severity. TCR diversity was measured using clonality, an index defined as the inverted normalized Shannon entropy.
Results: Highly clonal TCR repertoires correlated with age and comorbidities. Using our meta-database approach, we found that vaccinated participants hospitalized with infection had the most restricted SARS-CoV-2-specific CD8 TCR repertoire. However, TCRB with predicted specificity to non-spike SARS-CoV-2 proteins dominated the response, even in vaccinated participants. We identified a peptide sequence in the ORF10 accessory protein that was more frequently recognized in study participants with mild disease. Conversely, CD8 T cell recognition of a peptide sequence in ORF1ab more closely correlated with severe disease.
Discussion: Overarchingly, TCR repertoire analysis revealed that CD8 T cells responding to SARS-CoV-2 broadly recognize epitopes across the SARS-CoV-2 proteome, and provided opportunities to identify epitopes associated with disease.
Keywords: CD8 T cells; SARS-CoV-2; T cell receptor (TCR); T cell receptor sequencing; vaccination.
. 2025 Oct 2:16:1576903.
doi: 10.3389/fimmu.2025.1576903. eCollection 2025. Patterns of restricted TCR usage following SARS-CoV-2 vaccination and severe disease
Emily Parsons[SUP] 1 [/SUP], Zhongyan Lu[SUP] 1 2 [/SUP], Stephanie A Richard[SUP] 2 3 [/SUP], Amanda Zelkoski[SUP] 1 2 [/SUP], Janifer Le[SUP] 1 2 [/SUP], Naraen Palanikumar[SUP] 1 2 [/SUP], Phuong Nguyen[SUP] 1 2 [/SUP], Camille Alba[SUP] 2 4 5 [/SUP], Gauthaman Sukumar[SUP] 2 4 5 [/SUP], John Rosenberger[SUP] 2 4 [/SUP], Xijun Zhang[SUP] 2 4 [/SUP], Timothy H Burgess[SUP] 3 [/SUP], Rhonda Colombo[SUP] 2 3 6 7 [/SUP], Katrin Mende[SUP] 2 3 8 [/SUP], Catherine Berjohn[SUP] 2 6 9 [/SUP], Nursat Epsi[SUP] 2 3 [/SUP], Brian K Agan[SUP] 2 3 [/SUP], David Tribble[SUP] 3 [/SUP], David A Lindholm[SUP] 6 8 [/SUP], Clifton L Dalgard[SUP] 4 5 [/SUP], Simon D Pollett[SUP] 2 3 [/SUP], Allison M W Malloy[SUP] 1 [/SUP]; EPICC COVID-19 Cohort Study Group
Affiliations
- PMID: 41112294
- PMCID: PMC12528067
- DOI: 10.3389/fimmu.2025.1576903
Introduction: T cells influence COVID-19 severity and establish long-lasting immune memory in response to vaccination and infection. The diversity of the T cell repertoire, and complexity of T cell epitope recognition, make it challenging to define protective epitope-specific T cells. In this study, we created a highly specific TCR meta-database to identify T cell epitopes from the nearly complete SARS-CoV-2 proteome and determine whether vaccination with mRNA vaccines influenced the TCR repertoire.
Methods: Using this meta-database, we analyzed immunosequencing data of genomic DNA to define the variable region of T cell receptor (TCR) b chain (TCRB) sequences among participants in a longitudinal COVID-19 cohort study. The TCR repertoire was compared between participants who were vaccinated or unvaccinated against SARS-CoV-2 and stratified by disease severity. TCR diversity was measured using clonality, an index defined as the inverted normalized Shannon entropy.
Results: Highly clonal TCR repertoires correlated with age and comorbidities. Using our meta-database approach, we found that vaccinated participants hospitalized with infection had the most restricted SARS-CoV-2-specific CD8 TCR repertoire. However, TCRB with predicted specificity to non-spike SARS-CoV-2 proteins dominated the response, even in vaccinated participants. We identified a peptide sequence in the ORF10 accessory protein that was more frequently recognized in study participants with mild disease. Conversely, CD8 T cell recognition of a peptide sequence in ORF1ab more closely correlated with severe disease.
Discussion: Overarchingly, TCR repertoire analysis revealed that CD8 T cells responding to SARS-CoV-2 broadly recognize epitopes across the SARS-CoV-2 proteome, and provided opportunities to identify epitopes associated with disease.
Keywords: CD8 T cells; SARS-CoV-2; T cell receptor (TCR); T cell receptor sequencing; vaccination.