scholarly journals Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control

2016 ◽  
Vol 196 (6) ◽  
pp. 2666-2676 ◽  
Author(s):  
Maria A. Steffensen ◽  
Louise H. Pedersen ◽  
Marie L. Jahn ◽  
Karen N. Nielsen ◽  
Jan P. Christensen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Viral Challenge ◽  
Virus Control

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.

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

2016 ◽  
Vol 34 (4) ◽  
pp. 396-409 ◽  
Author(s):  
Katja Nitschke ◽  
Hendrik Luxenburger ◽  
Muthamia M. Kiraithe ◽  
Robert Thimme ◽  
Christoph Neumann-Haefelin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hepatitis B ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Acute Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Hcv Infection ◽  
T Cell Epitopes

Approximately 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) worldwide and are thus at high risk of progressive liver disease, leading to liver fibrosis, cirrhosis and ultimately hepatocellular cancer. Virus-specific CD8+ T-cells play a major role in viral clearance in >90% of adult patients who clear HBV and in approximately 30% of patients who clear HCV in acute infection. However, several mechanisms contribute to the failure of the adaptive CD8+ T-cell response in those patients who progress to chronic infection. These include viral mutations leading to escape from the CD8+ T-cell response as well as exhaustion and dysfunction of virus-specific CD8+ T-cells. Antiviral efficacy of the virus-specific CD8+ T-cell response also strongly depends on its restriction by specific human leukocyte antigens (HLA) class I alleles. Our review will summarize the role of HLA-A, B and C-restricted CD8+ T-cells in HBV and HCV infection. Due to the current lack of a comprehensive database of HBV- and HCV-specific CD8+ T-cell epitopes, we also provide a summary of the repertoire of currently well-described HBV- and HCV-specific CD8+ T-cell epitopes. A better understanding of the factors that contribute to the success or failure of virus-specific CD8+ T-cells may help to develop new therapeutic options for HBV eradication in patients with chronic HBV infection (therapeutic vaccination and/or immunomodulation) as well as a prophylactic vaccine against HCV infection.

scholarly journals Amino Acid Substitutions within HLA-B*27-Restricted T Cell Epitopes Prevent Recognition by Hepatitis Delta Virus-Specific CD8+T Cells

2018 ◽  
Vol 92 (13) ◽  
pp. e01891-17 ◽  
Author(s):  
Hadi Karimzadeh ◽  
Muthamia M. Kiraithe ◽  
Anna D. Kosinska ◽  
Manuel Glaser ◽  
Melanie Fiedler ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Hepatitis Delta Virus ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Viral Escape ◽  
T Cell Epitopes ◽  
Hepatitis Delta ◽  
Hdv Infection ◽  
Delta Virus

ABSTRACTVirus-specific CD8 T cell response seems to play a significant role in the outcome of hepatitis delta virus (HDV) infection. However, the HDV-specific T cell epitope repertoire and mechanisms of CD8 T cell failure in HDV infection have been poorly characterized. We therefore aimed to characterize HDV-specific CD8 T cell epitopes and the impacts of viral mutations on immune escape. In this study, we predicted peptide epitopes binding the most frequent human leukocyte antigen (HLA) types and assessed their HLA binding capacities. These epitopes were characterized in HDV-infected patients by intracellular gamma interferon (IFN-γ) staining. Sequence analysis of large hepatitis delta antigen (L-HDAg) and HLA typing were performed in 104 patients. The impacts of substitutions within epitopes on the CD8 T cell response were evaluated experimentally and byin silicostudies. We identified two HLA-B*27-restricted CD8 T cell epitopes within L-HDAg. These novel epitopes are located in a relatively conserved region of L-HDAg. However, we detected molecular footprints within the epitopes in HLA-B*27-positive patients with chronic HDV infections. The variant peptides were not cross-recognized in HLA-B*27-positive patients with resolved HDV infections, indicating that the substitutions represent viral escape mutations. Molecular modeling of HLA-B*27 complexes with the L-HDAg epitope and its potential viral escape mutations indicated that the structural and electrostatic properties of the bound peptides differ considerably at the T cell receptor interface, which provides a possible molecular explanation for the escape mechanism. This viral escape from the HLA-B*27-restricted CD8 T cell response correlates with a chronic outcome of hepatitis D infection. T cell failure resulting from immune escape may contribute to the high chronicity rate in HDV infection.IMPORTANCEHepatitis delta virus (HDV) causes severe chronic hepatitis, which affects 20 million people worldwide. Only a small number of patients are able to clear the virus, possibly mediated by a virus-specific T cell response. Here, we performed a systematic screen to define CD8 epitopes and investigated the role of CD8 T cells in the outcome of hepatitis delta and how they fail to eliminate HDV. Overall the number of epitopes identified was very low compared to other hepatotropic viruses. We identified, two HLA-B*27-restricted epitopes in patients with resolved infections. In HLA-B*27-positive patients with chronic HDV infections, however, we detected escape mutations within these identified epitopes that could lead to viral evasion of immune responses. These findings support evidence showing that HLA-B*27 is important for virus-specific CD8 T cell responses, similar to other viral infections. These results have implications for the clinical prognosis of HDV infection and for vaccine development.

scholarly journals Retinoic Acid as a Vaccine Adjuvant Enhances CD8+ T Cell Response and Mucosal Protection from Viral Challenge

2011 ◽  
Vol 85 (16) ◽  
pp. 8316-8327 ◽  
Author(s):  
X. Tan ◽  
J. L. Sande ◽  
J. S. Pufnock ◽  
J. N. Blattman ◽  
P. D. Greenberg
Keyword(s):  
Retinoic Acid ◽  
T Cell ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Vaccine Adjuvant ◽  
Mucosal Protection ◽  
Viral Challenge

scholarly journals Identification of Naturally Processed Mumps Virus Epitopes by Mass Spectrometry: Confirmation of Multiple CD8+ T-Cell Responses in Mumps Patients

2019 ◽  
Author(s):  
Jelle de Wit ◽  
Maarten E Emmelot ◽  
Hugo Meiring ◽  
Jacqueline A M van Gaans-van den Brink ◽  
Cécile A C M van Els ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Mumps Virus ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses

Abstract Background The re-emergence of mumps among vaccinated young adults has become a global issue. Besides waning of antibody responses, suboptimal induction of T-cell responses may reduce protection. In a recent study, we observed a dominant polyfunctional CD8+ T-cell response after natural mumps virus (MuV) infection that was not present after vaccination. Unraveling the MuV epitope repertoire can provide insight in the specificity, functionality, and breadth of the T-cell response against MuV. Methods Peptides were eluted from human leukocyte antigen (HLA) class I molecules of MuV-infected cells and characterized by advanced mass spectrometry. Selected identified MuV peptides were tested for in vitro and ex vivo immunogenicity. Results In this study, we identified a broad landscape of 83 CD8+ T-cell epitopes of MuV, 41 of which were confirmed based on synthetic peptide standards. For 6 epitopes, we showed induction of an HLA-A*02-restriced CD8+ T-cell response. Moreover, robust T-cell responses against 5 selected MuV epitopes could be detected in all tested mumps patients using peptide/HLA-A*02:01 dextramers. Conclusions The identified CD8+ T-cell epitopes will help to further characterize MuV-specific T-cell immunity after natural MuV infection or vaccination. These MuV epitopes may provide clues for a better understanding of, and possibly for preventing, mumps vaccine failure. We identified for the first time 41 mumps virus (MuV)-specific HLA-A*02 epitopes. For 6 epitopes, CD8+ T-cell responses were confirmed in T cells derived from several mumps cases, and MuV-specific CD8+ T cells could be identified by peptide/dextramer staining.

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