Measures of epitope binding degeneracy from T cell receptor repertoires DOI Creative Commons
Andreas Mayer, Curtis G. Callan

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(4)

Published: Jan. 17, 2023

Adaptive immunity is driven by specific binding of hypervariable receptors to diverse molecular targets. The sequence diversity and targets are both individually known but because multiple can recognize the same target, a measure effective “functional” human immune system has remained elusive. Here, we show that near-coincidences within T cell bind epitopes provide new window into this problem allow quantification how probability covaries with sequence. We find near-coincidence statistics epitope-specific repertoires imply degeneracy amino acid changes in receptor consistent across disparate experiments. Paired data on chains heterodimeric particularly revealing since simultaneous rare they be exploited estimate number epitope responses created memory compartment. In addition, paired-chain coincidences strongly suppressed donors different leukocyte antigens, evidence for central role antigen-driven selection making paired chain public. These results demonstrate power coincidence analysis reveal determinants repertoires.

Language: Английский

Benchmarking solutions to the T-cell receptor epitope prediction problem: IMMREP22 workshop report DOI Creative Commons
Pieter Meysman, Justin Barton, Barbara Bravi

et al.

ImmunoInformatics, Journal Year: 2023, Volume and Issue: 9, P. 100024 - 100024

Published: Feb. 3, 2023

Many different solutions to predicting the cognate epitope target of a T-cell receptor (TCR) have been proposed. However several questions on advantages and disadvantages these approaches remain unresolved, as most methods only evaluated within context their initial publications data sets. Here, we report findings first public TCR-epitope prediction benchmark performed 23 models in ImmRep 2022 specificity workshop. This revealed that use paired-chain alpha-beta, well CDR1/2 or V/J information, when available, improves classification obtained with CDR3 data, independent underlying approach. In addition, found straight-forward distance-based can achieve respectable performance compared more complex machine-learning models. Finally, highlight need for truly follow-up provide recommendations design such next benchmark.

Language: Английский

Citations

68
Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection DOI Creative Commons
Fei Gao, Vamsee Mallajosyula, Prabhu S. Arunachalam

et al.

Immunity, Journal Year: 2023, Volume and Issue: 56(4), P. 864 - 878.e4

Published: March 16, 2023

T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific cell responses for dominant CD4

Language: Английский

Citations

59
Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults DOI
Helen R. Wagstaffe, Ryan S. Thwaites, Arnold Reynaldi

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(92)

Published: Feb. 9, 2024

Human infection challenge permits in-depth, early, and pre-symptomatic characterization of the immune response, enabling identification factors that are important for viral clearance. Here, we performed intranasal inoculation 34 young adult, seronegative volunteers with a pre-Alpha severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Of these participants, 18 (53%) became infected showed an interferon-dominated mediator response divergent kinetics between nasal systemic sites. Peripheral CD4

Language: Английский

Citations

29
An intranasal combination vaccine induces systemic and mucosal immunity against COVID-19 and influenza DOI Creative Commons
Man Xing, Gaowei Hu, Xiang Wang

et al.

npj Vaccines, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 21, 2024

Abstract Despite prolonged surveillance and interventions, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) influenza viruses continue to pose a global health burden. Thus, we developed chimpanzee adenovirus-based combination vaccine, AdC68-HATRBD, with dual specificity against SARS-CoV-2 virus. When used as standalone intranasal immunization AdC68-HATRBD induced comprehensive potent immune responses consisting of immunoglobin (Ig) G, mucosal IgA, neutralizing antibodies, memory T cells, which protected mice from BA.5.2 pandemic H1N1 infections. heterologous booster, markedly improved protective response licensed or vaccine. Therefore, whether administered intranasally booster this vaccine is valuable strategy enhance overall efficacy by inducing robust systemic responses, thereby conferring lines immunological defenses for these two viruses.

Language: Английский

Citations

17
COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation DOI Creative Commons
Matthias Reinscheid, Hendrik Luxenburger, Vivien Karl

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 8, 2022

Abstract Immunization with two mRNA vaccine doses elicits robust spike-specific CD8 + T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction booster campaigns. However, effect on response remains unclear. Here we show that cells are activated and expanded in all analyzed individuals receiving 3 rd 4 th shots. This boost is followed by a contraction phase lasts only for about 30-60 days. The memory stem pool not affected vaccination. Both breakthrough infections Delta Omicron rapidly reactivate cells. In contrast, neutralizing antibody responses display little towards Omicron. Thus, transient effector while long-term conserved to mount recall targeting emerging variants concern.

Language: Английский

Citations

59
Improved control of SARS-CoV-2 by treatment with a nucleocapsid-specific monoclonal antibody DOI Creative Commons
Tanushree Dangi, Sarah Sanchez, Jacob Class

et al.

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(23)

Published: Oct. 11, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and also only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine then transferred sera from these into naive mice, followed by challenge show that received or mAb exhibited enhanced control of Nucleocapsid-specific elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) infected cells. To our knowledge, findings provide demonstration literature specific nucleocapsid clearance, providing rationale clinical evaluation therapies treat COVID-19.

Language: Английский

Citations

55
SARS-CoV-2-specific T cell memory with common TCRαβ motifs is established in unvaccinated children who seroconvert after infection DOI Creative Commons
Louise C. Rowntree, Thi H. O. Nguyen, Łukasz Kedzierski

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(7), P. 1299 - 1315.e4

Published: June 8, 2022

As the establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory in children remains largely unexplored, we recruited convalescent COVID-19 and adults to define their circulating SARS-CoV-2-specific CD4

Language: Английский

Citations

44
Resolving SARS-CoV-2 CD4+ T cell specificity via reverse epitope discovery DOI Creative Commons
Mikhail V. Pogorelyy, Elisa Rosati, Anastasia A. Minervina

et al.

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(8), P. 100697 - 100697

Published: July 1, 2022

The current strategy to detect immunodominant T cell responses focuses on the antigen, employing large peptide pools screen for functional activation. However, these approaches are labor and sample intensive scale poorly with increasing size of pathogen peptidome. receptors (TCRs) recognizing same epitope frequently have highly similar sequences, thus, presence sequence similarity clusters in TCR repertoire likely identify most public responses. Here, we perform a meta-analysis large, publicly available single-cell bulk datasets from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals CD4

Language: Английский

Citations

44
Impact of SARS-CoV-2 exposure history on the T cell and IgG response DOI Creative Commons
Roanne Keeton, Marius B. Tincho, Akiko Suzuki

et al.

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 4(1), P. 100898 - 100898

Published: Dec. 22, 2022

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposures, from infection or vaccination, can potently boost spike antibody responses. Less is known about the impact of repeated exposures on T cell Here, we compare prevalence and frequency peripheral SARS-CoV-2-specific immunoglobulin G (IgG) responses in 190 individuals with complex SARS-CoV-2 exposure histories. As expected, an increasing number significantly enhances magnitude IgG responses, while improve responders but have less spike-specific frequencies circulation. Moreover, find that nature (rather than order vaccination) shape immune response, CD4 cells displaying a greater polyfunctional potential following hybrid immunity compared vaccination only. Characterizing adaptive evolving viral immunological landscape may inform vaccine strategies to elicit optimal as pandemic progress.

Language: Английский

Citations

43
Defending against SARS-CoV-2: The T cell perspective DOI Creative Commons
Patricia Almendro-Vázquez, Rocío Laguna‐Goya,

Estela Paz‐Artal

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Jan. 27, 2023

SARS-CoV-2-specific T cell response has been proven essential for viral clearance, COVID-19 outcome and long-term memory. Impaired early cell-driven immunity leads to a severe form of the disease associated with lymphopenia, hyperinflammation imbalanced humoral response. Analyses acute SARS-CoV-2 infection have revealed that mild course is characterized by an induction specific cells within first 7 days symptoms, coordinately followed antibody production effective control infection. In contrast, patients who do not develop cellular initiate immune subsequent high levels antibodies, symptoms. Yet, delayed persistent bystander CD8+ activation also reported in hospitalized could be driver lung pathology. Literature supports maintenance appears more stable than titters. Up date, virus-specific memory detected 22 months post-symptom onset, predominant IL-2 compared IFN-γ. Furthermore, responses are conserved against emerging variants concern (VoCs) while these mostly able evade responses. This partly explained HLA polymorphism whereby epitope repertoire recognized differ among individuals, greatly decreasing likelihood escape. Current COVID-19-vaccination shown elicit Th1-driven spike-specific response, as does natural infection, which provides substantial protection death. addition, mucosal vaccination induce strong adaptive both locally systemically protect VoCs animal models. The optimization vaccine formulations including variety regions, innovative adjuvants or diverse administration routes result desirable enhanced memory, help prevent breakthrough infections. summary, increasing evidence highlights relevance monitoring only levels, correlate after and/or vaccination. Moreover, it may better identify target populations benefit most from booster doses personalize strategies.

Language: Английский

Citations

38