Vaccination Reshapes the Virus-Specific T Cell Repertoire in Unexposed Adults

Pan, Yi-Gen; Aiamkitsumrit, Benjamas; Bartolo, Laurent; Wang, Yifeng; Lavery, Criswell; Marc, Adam; Holec, Patrick V.; Eilola, Theresa; Gimotty, Phyllis A.; Hensley, Scott E.; Antia, Rustom; Zarnitsyna, Veronika I.; Birnbaum, Michael E.; Su, Laura F.

doi:10.2139/ssrn.3720303

Cited by 3 publications

(13 citation statements)

References 49 publications

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“…1F). To examine how SARS-CoV-2 specific T cells differ from a true antigen-inexperienced population, we compared them to T cells that recognized YFV in YFV naïve individuals (18) . Unlike coronaviruses, YFV-related viruses are uncommon in the United States.…”

Section: Resultsmentioning

confidence: 99%

“…Instead, the abundance of pre-existing memory cells correlated with donor age, suggesting a contribution from the broader antigen experiences that accumulate over time (Fig.S2C). To investigate if T cells are receiving stimulatory signals at baseline, we analyzed activation state using ICOS (18, 33) . We found ICOS expressed on a subset of SARS-CoV-2 tetramer + cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The composition of the pre-immune repertoire directly impacts post-immune responses. We had previously examined T cell responses in primary immunization with YFV vaccine and identified dynamic changes after vaccination that depended on cells’ pre-existing state (18) . Here we performed high dimensional phenotypic analyses on tetramer + cells to further delineate the differentiation states of SARS-CoV-2 specific precursor cells.…”

Section: Discussionmentioning

confidence: 99%

“…The goal of the study was to define the pre-existing state of SARS-CoV-2 specific T cells. Cryopreserved cells were stored from past collection from the Stanford Blood Bank or prior studies at the University of Pennsylvania (18) . Subject characteristics are shown in Table S1.…”

Section: Methodsmentioning

confidence: 99%

“…What remains less clear is how the environment shapes human immune responses to SARS-CoV-2 and other pathogens. We and others have previously reported that memory T cells recognize human immunodeficiency virus (HIV), cytomegalovirus (CMV), herpes simplex virus (HSV), and yellow fever virus (YFV) in people who tested negative for these infections (16)(17)(18). Prior studies have also identified T cells that recognized SARS-CoV-2 in unexposed individuals (15,(19)(20)(21)(22)(23)(24)(25).…”

Section: Sars-cov-2 Infection (Covid-19mentioning

confidence: 99%

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SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

Bartolo

Afroz

Pan

et al. 2021

Preprint

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The baseline composition of T cells directly impacts later response to a pathogen, but the complexity of precursor states remains poorly defined. Here we examined the baseline state of SARS-CoV-2 specific T cells in unexposed individuals. SARS-CoV-2 specific CD4+ T cells were identified in pre-pandemic blood samples by class II peptide-MHC tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2 specific T cells that expressed memory phenotype markers, including memory cells with gut homing receptors. T cell clones generated from tetramer-labeled cells cross-reacted with bacterial peptides and responded to stool lysates in a MHC-dependent manner. Integrated phenotypic analyses revealed additional precursor diversity that included T cells with distinct polarized states and trafficking potential to other barrier tissues. Our findings illustrate a complex pre-existing memory pool poised for immunologic challenges and implicate non-infectious stimuli from commensal colonization as a factor that shapes pre-existing immunity.One Sentence SummaryPre-existing immunity to SARS-CoV-2 contains a complex pool of precursor lymphocytes that include differentiated cells with broad tissue tropism and the potential to cross-react with commensal antigens.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Sars-cov-2 Infection (Covid-19mentioning

confidence: 99%

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SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

Bartolo

Afroz

Pan

et al. 2021

Preprint

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The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

Mohammed

Meadows²,

Hekmaty

et al. 2021

Preprint

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Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

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SARS-CoV-2–specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

et al. 2022

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The baseline composition of T cells directly impacts later response to pathogens, but the complexity of precursor states remains poorly defined. Here, we examined the baseline state of SARS-CoV-2-specific T cells in unexposed individuals. SARS-CoV-2-specific CD4 + T cells were identified in pre-pandemic blood samples by class II peptide-MHC tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2-specific T cells that expressed memory phenotype markers. Integrated phenotypic analyses demonstrated diverse pre-existing memory states that included cells with distinct polarization states and trafficking potential to barrier tissues. T cell clones generated from tetramer-labeled cells cross-reacted with antigens from commensal bacteria in the skin and gastrointestinal tract. Direct ex vivo tetramer staining for one spike-specific population showed a similar level of cross-reactivity to sequences from endemic coronavirus and commensal bacteria. These data highlight the complexity of precursor T cell repertoire and implicate non-infectious exposures to common microbes as a key factor that shapes human pre-existing immunity to SARS-CoV-2.

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Vaccination Reshapes the Virus-Specific T Cell Repertoire in Unexposed Adults

Cited by 3 publications

References 49 publications

SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

SARS-CoV-2-specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

SARS-CoV-2–specific T cells in unexposed adults display broad trafficking potential and cross-react with commensal antigens

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