scholarly journals A systematic, unbiased mapping of CD8+ and CD4+ T cell epitopes in Yellow Fever vaccinees

2020 ◽  
Author(s):  
Anette Stryhn ◽  
Michael Kongsgaard ◽  
Michael Rasmussen ◽  
Mikkel Nors Harndahl ◽  
Thomas Østerbye ◽  
...  
Keyword(s):  
T Cell ◽  
Yellow Fever ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Hla Class I ◽  
Class I ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Epitope Discovery

1.AbstractExamining CD8+ and CD4+ T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8+ and 50 CD4+ T cell epitopes, many inducing strong and prevalent (i.e. immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4+ T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4+ T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4+ T cell responses. Our T cell epitope discovery approach uses a combination of 1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4+ and/or CD8+ T cell epitopes, 2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, 3) generation of peptide-HLA tetramers to identify T cell epitopes, and 4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4+ and CD8+ T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g. SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses.

scholarly journals Public T-cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles

2021 ◽  
Author(s):  
Saskia Meyer ◽  
Isaac Blaas ◽  
Ravi Chand Bollineni ◽  
Marina Delic-Sarac ◽  
Trung T Tran ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Class I ◽  
T Cell Epitopes ◽  
Low Frequencies ◽  
Cell Responses

T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. Here, we investigate CD8 T-cell responses to 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identify nine conserved SARS-CoV-2 specific epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians, to which responding CD8 T cells are detected in 70-100% of convalescents expressing the relevant HLA allele, including two novel epitopes. We find a strong correlation between immunoprevalence and immunodominance. Using a new algorithm, we predict that a vaccine including these epitopes would induce a T cell response in 83% of Caucasians. Significance Statement: Vaccines that induce broad T-cell responses may boost immunity as protection from current vaccines against SARS-CoV-2 is waning. From a manufacturing standpoint, and to deliver the highest possible dose of the most immunogenic antigens, it is rational to limit the number of epitopes to those inducing the strongest immune responses in the highest proportion of individuals in a population. Our data show that the CD8 T cell response to SARS-CoV-2 is more focused than previously believed. We identify nine conserved SARS-CoV-2 specific CD8 T cell epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians and demonstrate that seven of these are endogenously presented.

scholarly journals Landscape and selection of vaccine epitopes in SARS-CoV-2

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Christof C. Smith ◽  
Kelly S. Olsen ◽  
Kaylee M. Gentry ◽  
Maria Sambade ◽  
Wolfgang Beck ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Sequence Conservation ◽  
Conformational Space ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
B Cell Epitope

Abstract Background Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE). Methods We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. Results From 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8+ and 284 CD4+ T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides. Conclusions Overall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.

scholarly journals Identification of HCMV-derived T cell epitopes in seropositive individuals through viral deletion models

2019 ◽  
Vol 217 (3) ◽  
Author(s):  
Maren Lübke ◽  
Stefanie Spalt ◽  
Daniel J. Kowalewski ◽  
Cosima Zimmermann ◽  
Liane Bauersfeld ◽  
...  
Keyword(s):  
T Cell ◽  
Functional Characterization ◽  
T Cell Responses ◽  
Hla Class I ◽  
Class I ◽  
T Cell Epitopes ◽  
Systematic Assessment ◽  
Memory T Cell ◽  
Cell Responses ◽  
Novel Approach

In healthy individuals, immune control of persistent human cytomegalovirus (HCMV) infection is effectively mediated by virus-specific CD4+ and CD8+ T cells. However, identifying the repertoire of T cell specificities for HCMV is hampered by the immense protein coding capacity of this betaherpesvirus. Here, we present a novel approach that employs HCMV deletion mutant viruses lacking HLA class I immunoevasins and allows direct identification of naturally presented HCMV-derived HLA ligands by mass spectrometry. We identified 368 unique HCMV-derived HLA class I ligands representing an unexpectedly broad panel of 123 HCMV antigens. Functional characterization revealed memory T cell responses in seropositive individuals for a substantial proportion (28%) of these novel peptides. Multiple HCMV-directed specificities in the memory T cell pool of single individuals indicate that physiologic anti-HCMV T cell responses are directed against a broad range of antigens. Thus, the unbiased identification of naturally presented viral epitopes enabled a comprehensive and systematic assessment of the physiological repertoire of anti-HCMV T cell specificities in seropositive individuals.

Differential escape pathways from the dominant CD8 T cell epitope in HBV core18 – 27 depend on the HLA class I genotype

2018 ◽  
Vol 56 (01) ◽  
pp. E2-E89
Author(s):  
J Brinkmann ◽  
T Schwarz ◽  
H Kefalakes ◽  
J Schulze zur Wiesch ◽  
A Kraft ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Class I ◽  
T Cell Epitope

scholarly journals Strong HLA Class I–Restricted T Cell Responses in Dengue Hemorrhagic Fever: A Double‐Edged Sword?

2001 ◽  
Vol 184 (11) ◽  
pp. 1369-1373 ◽  
Author(s):  
Hsin Loke ◽  
Delia B. Bethell ◽  
C. X. T. Phuong ◽  
Minh Dung ◽  
Joerg Schneider ◽  
...  
Keyword(s):  
T Cell ◽  
Dengue Hemorrhagic Fever ◽  
T Cell Responses ◽  
Hla Class I ◽  
Hemorrhagic Fever ◽  
Class I ◽  
Cell Responses

scholarly journals Cross-Priming of T Cell Responses by Synthetic Microspheres Carrying a CD8+ T Cell Epitope Requires an Adjuvant Signal

2005 ◽  
Vol 174 (6) ◽  
pp. 3432-3439 ◽  
Author(s):  
Florence Boisgérault ◽  
Paloma Rueda ◽  
Cheng Ming Sun ◽  
Sandra Hervas-Stubbs ◽  
Marie Rojas ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitope ◽  
Cell Responses

scholarly journals Induction of Polyomavirus-Specific CD8+T Lymphocytes by Distinct Dendritic Cell Subpopulations

2001 ◽  
Vol 75 (1) ◽  
pp. 544-547 ◽  
Author(s):  
Donald R. Drake ◽  
Mandy L. Shawver ◽  
Annette Hadley ◽  
Eric Butz ◽  
Charles Maliszewski ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cell Epitope ◽  
T Cell Responses ◽  
T Cell Epitope ◽  
Cell Responses ◽  
Cd8 T Lymphocytes ◽  
Cell Subpopulations ◽  
Antigen Presenting

ABSTRACT Dendritic cells are pivotal antigen-presenting cells for generating adaptive T-cell responses. Here, we show that dendritic cells belonging to either the myeloid-related or lymphoid-related subset are permissive for infection by mouse polyomavirus and, when loaded with a peptide corresponding to the immunodominant anti-polyomavirus CD8+T-cell epitope or infected by polyomavirus, are each capable of driving expansion of primary polyomavirus-specific CD8+ T-cell responses in vivo.

HLA Class I Ligandome Analysis In Acute Myeloid Leukemia – Novel T-Cell Epitopes For Peptide-Based Immunotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5431-5431
Author(s):  
Stickel S. Juliane ◽  
Claudia Berlin ◽  
Daniel J. Kowalewski ◽  
Heiko Schuster ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Peptide Vaccine ◽  
T Cell Responses ◽  
Hla Class I ◽  
Class I ◽  
Isolation And Identification ◽  
Cell Responses ◽  
Healthy Donors ◽  
Hla Ligands

Abstract Data regarding the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (SCT) and donor lymphocyte infusion strongly suggest that T lymphocytes play a major role in the rejection of leukemic cells. Immunotherapy directed against leukemia- associated antigens might elicit specific immune responses that may serve to eliminate minimal residual disease after chemotherapy, or enhance the GVL effect after SCT. To achieve this goal there is need to identify appropriate leukemia associated HLA ligands, which are able to induce specific T cell responses. We here aimed to characterize the HLA class I ligandome in AML patients to provide novel tumor associated antigens (TAA) for peptide-based immunotherapy employing our recently implemented approach of direct isolation and identification of naturally presented HLA ligands by affinity chromatography and mass spectrometry (LC-MS/MS) in AML (Stickel et.al., abstract in Blood 2012). Absolute HLA surface expression on AML cells and autologous monocytes and granulocytes was quantified by flow cytometry. HLA class I ligands were isolated from AML cells as well as bone marrow and peripheral blood mononuclear cell (BMNCs/PBMCs) of healthy donors. LC-MS/MS peptide analysis provided qualitative and semi-quantitative information regarding the composition of the respective ligandomes. Comparative analysis of malignant and benign samples served to identify ligandome-derived TAA (LiTAA) and to select peptide vaccine candidates. The most abundantly detected peptide candidates were checked for immunogenicity by ELISpot and confirmed by intracellular interferon-g staining of CD8+ T-cells. Meanwhile 15 AML patients (8 FLT3-ITD mutant) and 35 healthy donors were analyzed. We observed overexpression of HLA class I and II on AML cells as compared to autologous monocytes and granulocytes, with the level of significance reached for HLA class II (p=0,04). A total of more than 12,000 AML derived HLA ligands representing >6,000 different source proteins were identified; of which 2,220 were exclusively represented in AML, but not in healthy PBMC/BMNC. Data mining for broadly represented LiTAA pinpointed 98 TAA as most promising targets. HLA ligands derived from these TAA were presented exclusively on more than 33% of all analyzed AML samples, amongst them already described TAA (e.g. JUP, FAF1) as well as several new leukemia-associated proteins (e.g. MTCH2, METTL7A). Subset analysis of the FLT3-ITD positive AML cohort revealed 21 LiTAA presented exclusively on more than 50% of FLT3-ITD positive AML cases. Additional screening for HLA ligands derived from described leukemia associated antigens revealed overrepresentation for e.g. FLT3, NUSAP, RHAMM and RGS5. Specific CD8+ T cell responses were detected against two A*03 epitope pools (pool 1: APLP2, DKGZ, FAF1, MTCH2; pool 2: KLF2, METTL7A, VCIP1, WIPI1) in AML patients. Notably, the chosen A*03 epitope pools did not elicit specific responses of CTL from healthy donors. Taken together, our HLA class I ligandome analysis in AML for the first time identified naturally presented HLA ligands from patients including a vast array of new leukemia associated antigens representing promising targets for a multipeptide-based immunotherapy approach in AML. Disclosures: No relevant conflicts of interest to declare.

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