Vaccination-induced T cell responses maintain polyclonality with high antigen receptor avidity
(1) Kocher K (2) Drost F (3) Tesfaye AM (4) Moosmann C (5) Schlein C (6) Grotz M (7) D'Ippolito E (8) Graw F (9) Spriewald B (10) Busch DH (11) Bogdan C (12) Tenbusch M (13) Schubert B (14) Schober K
In PBMC samples from 3x SARS-CoV-2 mRNA-vaccinated individuals, Kocher and Drost et al. used spike-specific dextramers to enrich CD8+ T cells for single-cell multiomics. The T cells were diverse and polyclonal, responded to WT and some mutated peptides, and new clonotypes arose after each vaccination. Functional avidity, measured after knock-in of spike-specific TCRs to primary T cells, was generally high and not correlated with clonal persistence or expansion. High TCR functionality and specificity for immunodominant epitopes associated with more differentiated T cell phenotypes, although stem-like cells also persisted.
Contributed by Alex Najibi
(1) Kocher K (2) Drost F (3) Tesfaye AM (4) Moosmann C (5) Schlein C (6) Grotz M (7) D'Ippolito E (8) Graw F (9) Spriewald B (10) Busch DH (11) Bogdan C (12) Tenbusch M (13) Schubert B (14) Schober K
In PBMC samples from 3x SARS-CoV-2 mRNA-vaccinated individuals, Kocher and Drost et al. used spike-specific dextramers to enrich CD8+ T cells for single-cell multiomics. The T cells were diverse and polyclonal, responded to WT and some mutated peptides, and new clonotypes arose after each vaccination. Functional avidity, measured after knock-in of spike-specific TCRs to primary T cells, was generally high and not correlated with clonal persistence or expansion. High TCR functionality and specificity for immunodominant epitopes associated with more differentiated T cell phenotypes, although stem-like cells also persisted.
Contributed by Alex Najibi
ABSTRACT: Clonal expansion is a hallmark of adaptive immunity and has been challenging to investigate in humans in a standardized manner compared with animal models. We studied a cohort of 29 healthy individuals who received three mRNA vaccinations against SARS-CoV-2 before a breakthrough infection. We characterized the magnitude, phenotype, and clonal composition of CD8 T cell responses against 16 epitope specificities by ELISpot; flow cytometry; and single-cell RNA, protein, and T cell receptor (TCR) sequencing. One hundred six TCRs from five epitope-specific repertoires were reexpressed and tested for peptide sensitivity. Whereas vaccination-recruited T cell repertoires were enriched for high-avidity TCRs, differential clonal expansion was not linked to fine avidity differences. Instead, maintenance of polyclonality ensured robustness in counteracting viral mutational escape through altered epitopes. Deciphering the functionality of human antigen-specific T cell repertoires instructs our understanding of human T cell biology and may guide the development of vaccines and other immunotherapies.
Author Info:
(1) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlang
en, Germany. (2) Institute of Computational Biology, Helmholtz Zentrum Mnchen - German Research Center for Environmental Health, Neuherberg, Germany. School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany. (3) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. (4) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. (5) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. (6) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. (7) Institute for Medical Microbiology, Immunology, and Hygiene, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Center for Infection Research (Deutsches Zentrum fr Infektionsforschung, DZIF), Partner Site Munich, Munich, Germany. (8) Department of Internal Medicine 5, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt (FAU), Erlangen-Nrnberg, Erlangen, Germany. Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg and Universittsklinikum Erlangen, Erlangen, Germany. (9) Department of Internal Medicine 5, Universittsklinikum Erlangen and Friedrich-Alexander-Universitt (FAU), Erlangen-Nrnberg, Erlangen, Germany. (10) Institute for Medical Microbiology, Immunology, and Hygiene, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Center for Infection Research (Deutsches Zentrum fr Infektionsforschung, DZIF), Partner Site Munich, Munich, Germany. (11) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. FAU Profile Center Immunomedicine, FAU Erlangen-Nrnberg, Erlangen, Germany. (12) FAU Profile Center Immunomedicine, FAU Erlangen-Nrnberg, Erlangen, Germany. Institute of Clinical and Molecular Virology, Universittsklinikum Erlangen, Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. (13) Institute of Computational Biology, Helmholtz Zentrum Mnchen - German Research Center for Environmental Health, Neuherberg, Germany. Department of Mathematics, Technical University of Munich, Garching bei Mnchen, Germany. (14) Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universittsklinikum Erlangen und Friedrich-Alexander-Universitt (FAU) Erlangen-Nrnberg, Erlangen, Germany. FAU Profile Center Immunomedicine, FAU Erlangen-Nrnberg, Erlangen, Germany.
Citation: Sci Immunol 2025 Oct 3 10:eadu6730 Epub10/03/2025
