Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination
- University of Antwerp, Belgium
- Antwerp University Hospital, Belgium
- St. Jude Children's Research Hospital, United States
- Rode Kruis-Vlaanderen, Belgium
- Johnson and Johnson, Belgium
Abstract
Antigen recognition through the T cell receptor (TCR) αβ heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-naïve hosts. In this study, we use high-throughput sequencing of memory CD4 TCRβ repertoire and machine learning to show that individuals with preexisting vaccine-reactive memory CD4 T cell clonotypes elicited earlier and higher antibody titers and mounted a more robust CD4 T cell response to hepatitis B vaccine. In addition, integration of TCRβ sequence patterns into a hepatitis B epitope-specific annotation model can predict which individuals will have an early and more vigorous vaccine-elicited immunity. Thus, the presence of preexisting memory T cell clonotypes has a significant impact on immunity and can be used to predict immune responses to vaccination.
Data availability
The sequencing data that support the findings of this study have been deposited on Zenodo (https://doi.org/10.5281/zenodo.3989144).
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Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon vaccinationzenodo - 10.5281/zenodo.3989144.
Article and author information
Author details
Funding
University of Antwerp
- George Elias
- Esther Bartholomeus
- Nicolas De Neuter
Research Foundation Flanders
- Pieter Meysman
- Kris Laukens
- Benson Ogunjimi
American Lebanese Syrian Associated Charities
- Aisha Souquette
- Paul G Thomas
National Institute of Allergy and Infectious Diseases
- Aisha Souquette
- Paul G Thomas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Armita Nourmohammad, University of Washington, United States
Ethics
Human subjects: Protocols involving the use of human tissues were approved by the Ethics Committee of Antwerp University Hospital and University of Antwerp (Antwerp, Belgium), and all of the experiments were performed in accordance with the protocols
Version history
- Preprint posted: August 25, 2020 (view preprint)
- Received: March 14, 2021
- Accepted: January 7, 2022
- Accepted Manuscript published: January 25, 2022 (version 1)
- Accepted Manuscript updated: January 26, 2022 (version 2)
- Version of Record published: February 8, 2022 (version 3)
Copyright
© 2022, Elias et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Preexisting memory CD4 T cells in naïve individuals confer robust immunity upon hepatitis B vaccination
eLife 11:e68388.
https://doi.org/10.7554/eLife.68388
Further reading
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- Immunology and Inflammation
SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as ‘sustainers’), but not in ‘decliners’. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.
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Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.
