Adaptive immunity to human coronaviruses is widespread but low in magnitude

AbstractEndemic human coronaviruses (hCoV) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV-specific T cell memory in adults. We quantified CD4 T cell and antibody responses to hCoV spike antigens in 42 SARS-CoV-2 uninfected individuals. T cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS-CoV-2 cross-reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV-specific T cells exhibited a CCR6+ central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung draining lymph nodes. Overall, hCoV-specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus-specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS-CoV-2.

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Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

10.1101/2021.07.12.21260227 ◽

2021 ◽

Author(s):

Anastasia A Minervina ◽

Mikhail V Pogorelyy ◽

Allison M Kirk ◽

Emma Kaitlynn Allen ◽

Kim J Allison ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

T Cell Responses ◽

T Cell Response ◽

Critical Parameters ◽

T Cell Memory ◽

Cell Memory ◽

Cell Responses ◽

Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

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CD8 T cells induce T-bet–dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines

Blood ◽

10.1182/blood-2012-03-417733 ◽

2012 ◽

Vol 120 (23) ◽

pp. 4552-4559 ◽

Cited By ~ 21

Author(s):

Karine Serre ◽

Adam F. Cunningham ◽

Ruth E. Coughlan ◽

Andreia C. Lino ◽

Antal Rot ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Cd8 T Cells ◽

Cd4 T Cell ◽

T Helper ◽

T Helper 2 ◽

Cell Responses ◽

Cxcr3 Expression ◽

Ifn Γ ◽

Draining Lymph Nodes

Abstract Antibody-forming cells (AFCs) expressing the chemokine receptor CXCR3 are recruited to sites of inflammation where they help clear pathogens but may participate in autoimmune diseases. Here we identify a mechanism that induces CXCR3 expression by AFC and germinal center (GC) B cells. This happens when CD8 T cells are recruited into CD4 T cell–dependent B-cell responses. Ovalbumin-specific CD4 T cells (OTII) were transferred alone or with ovalbumin-specific CD8 T cells (OTI) and the response to subcutaneous alum-precipitated ovalbumin was followed in the draining lymph nodes. OTII cells alone induce T helper 2-associated class switching to IgG1, but few AFC or GC B cells express CXCR3. By contrast, OTI-derived IFN-γ induces most responding GC B cells and AFCs to express high levels of CXCR3, and diverse switching to IgG2a, IgG2b, with some IgG1. Up-regulation of CXCR3 by GC B cells and AFCs and their migration toward its ligand CXCL10 are shown to depend on B cells' intrinsic T-bet, a transcription factor downstream of the IFN-γR signaling. This model clarifies how precursors of long-lived AFCs and memory B cells acquire CXCR3 that causes their migration to inflammatory foci.

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Clearance of an Influenza A Virus by CD4+ T Cells Is Inefficient in the Absence of B Cells

Journal of Virology ◽

10.1128/jvi.72.1.882-885.1998 ◽

1998 ◽

Vol 72 (1) ◽

pp. 882-885 ◽

Cited By ~ 117

Author(s):

David J. Topham ◽

Peter C. Doherty

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Influenza A Virus ◽

Cell Response ◽

Influenza A ◽

T Cell Response ◽

T Cell Memory ◽

Cell Responses ◽

Homologous Challenge

ABSTRACT The primary CD8+ T-cell response protected most B-cell-deficient μMT mice against intranasal infection with the HKx31 influenza A virus. Prior exposure did not prevent reinfection upon homologous challenge, and the recall CD8+ T-cell response cleared the virus from the lung within 7 days. Depleting the CD8+ T cells substantially reduced the capacity of these primed mice to deal with the infection, in spite of evidence for established CD4+ T-cell memory. Thus, the control of this relatively mild influenza virus by both primary and secondary CD4+ T-cell responses is relatively inefficient in the absence of B cells and CD8+ T cells.

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BCL6-dependent TCF-1+ progenitor cells maintain effector and helper CD4 T cell responses to persistent antigen

10.1101/2021.08.06.455141 ◽

2021 ◽

Author(s):

Yu Xia ◽

Katalin Sandor ◽

Joy A Pai ◽

Bence Daniel ◽

Saravanan Raju ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Progenitor Cells ◽

Cd4 T Cells ◽

Population Based ◽

Cd4 T Cell ◽

Cell Responses ◽

Follicular Helper ◽

Persistent Antigen ◽

Draining Lymph Nodes

Shortly after priming, the fate of activated CD4 T cells is segregated into BCL6+ follicular helper T (Tfh) and BCL6- effector (Teff) cells. However, it remains unknown how these subsets are sustained in the presence of chronic antigen stimulation. Using a combination of single cell- and population-based approaches, we show that in chronic viral infection, activated CD4 T cells differentiate into BCL6-dependent TCF-1+ progenitor cells with superior capacity to expand and give rise to both Teff and Tfh. They share properties with progenitor-exhausted CD8 T cells and are required for the continued generation of Teff cells as antigen persists. In response to tumors, an analogous CD4 T cell population develops in draining lymph nodes. Our study reveals the heterogeneity and plasticity of CD4 T cells upon encountering persistent antigen and highlights their population dynamics through a stable bipotent intermediate state.

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Identification of Pertussis-Specific Effector Memory T Cells in Preschool Children

Clinical and Vaccine Immunology ◽

10.1128/cvi.00695-14 ◽

2015 ◽

Vol 22 (5) ◽

pp. 561-569 ◽

Cited By ~ 12

Author(s):

Lia de Rond ◽

Rose-Minke Schure ◽

Kemal Öztürk ◽

Guy Berbers ◽

Elisabeth Sanders ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Booster Vaccination ◽

T Cell Memory ◽

Effector Memory ◽

Memory Cells ◽

Cell Memory ◽

Cell Responses ◽

Specific Effector ◽

Effector Memory Cells

ABSTRACTWhooping cough remains a problem despite vaccination, and worldwide resurgence of pertussis is evident. Since cellular immunity plays a role in long-term protection against pertussis, we studied pertussis-specific T-cell responses. Around the time of the preschool acellular pertussis (aP) booster dose at 4 years of age, T-cell memory responses were compared in children who were primed during infancy with either a whole-cell pertussis (wP) or an aP vaccine. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with pertussis vaccine antigens for 5 days. T cells were characterized by flow-based analysis of carboxyfluorescein succinimidyl ester (CFSE) dilution and CD4, CD3, CD45RA, CCR7, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) expression. Before the aP preschool booster vaccination, both the proliferated pertussis toxin (PT)-specific CD4+and CD8+T-cell fractions (CFSEdim) were higher in aP- than in wP-primed children. Post-booster vaccination, more pertussis-specific CD4+effector memory cells (CD45RA−CCR7−) were induced in aP-primed children than in those primed with wP. The booster vaccination did not appear to significantly affect the T-cell memory subsets and functionality in aP-primed or wP-primed children. Although the percentages of Th1 cytokine-producing cells were alike in aP- and wP-primed children pre-booster vaccination, aP-primed children produced more Th1 cytokines due to higher numbers of proliferated pertussis-specific effector memory cells. At present, infant vaccinations with four aP vaccines in the first year of life result in pertussis-specific CD4+and CD8+effector memory T-cell responses that persist in children until 4 years of age and are higher than those in wP-primed children. The booster at 4 years of age is therefore questionable; this may be postponed to 6 years of age.

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Systematic examination of T cell responses to SARS-CoV-2 versus influenza virus reveals distinct inflammatory profile

10.1101/2020.08.27.20183319 ◽

2020 ◽

Author(s):

Jaclyn C Law ◽

Wan Koh ◽

Patrick Budylowski ◽

Jonah Lin ◽

FengYun Yue ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Strongly Correlated ◽

Ifn Gamma ◽

N Protein ◽

Cell Responses ◽

Follicular Helper ◽

Inflammatory Profile ◽

Central Memory Phenotype

There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. Here we investigated T cell recall responses to fully glycosylated Spike trimer, recombinant N protein as well as to S, N, M and E peptide pools in the early convalescent phase. All subjects showed SARS-CoV-2-specific T cell responses to at least one antigen. SARS-CoV-2-specific CD4+ T cells were primarily of the central memory phenotype and exhibited a lower IFN-[gamma] to TNF-[alpha] ratio compared to influenza-specific responses of the same donors, independent of disease severity. SARS-CoV-2-specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. High IL-10 production was noted in response to N protein, possibly contributing to immunosuppression, with potential implications for vaccine design. We observed granzyme B+/IFN-[gamma] CD4+ and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ responses predominating over CD8+ responses. Peripheral T follicular helper responses to S or N strongly correlated with serum neutralization assays as well as RBD-specific IgA. Overall, T cell responses to SARS-CoV-2 are robust, however, CD4+ Th1 responses predominate over CD8+ responses and are more inflammatory with a weaker Tfh response than influenza-specific CD4+ responses, potentially contributing to COVID-19 disease.

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