scholarly journals NS1 DNA vaccination protects against Zika infection through T cell–mediated immunity in immunocompetent mice

2019 ◽  
Vol 5 (12) ◽  
pp. eaax2388 ◽  
Author(s):  
B. Grubor-Bauk ◽  
D. K. Wijesundara ◽  
M. Masavuli ◽  
P. Abbink ◽  
R. L. Peterson ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Response ◽  
Viral Envelope ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Vaccine Immunogen ◽  
Zikv Infection ◽  
Cell Responses ◽  
Immunocompetent Mice

The causal association of Zika virus (ZIKV) with microcephaly, congenital malformations in infants, and Guillain-Barré syndrome in adults highlights the need for effective vaccines. Thus far, efforts to develop ZIKV vaccines have focused on the viral envelope. ZIKV NS1 as a vaccine immunogen has not been fully explored, although it can circumvent the risk of antibody-dependent enhancement of ZIKV infection, associated with envelope antibodies. Here, we describe a novel DNA vaccine encoding a secreted ZIKV NS1, that confers rapid protection from systemic ZIKV infection in immunocompetent mice. We identify novel NS1 T cell epitopes in vivo and show that functional NS1-specific T cell responses are critical for protection against ZIKV infection. We demonstrate that vaccine-induced anti-NS1 antibodies fail to confer protection in the absence of a functional T cell response. This highlights the importance of using NS1 as a target for T cell–based ZIKV vaccines.

scholarly journals Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein: A T Cell-Based Way-Out From the SARS-CoV-2 Variants Storm

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Boni ◽  
Davide Cavazzini ◽  
Angelo Bolchi ◽  
Marzia Rossi ◽  
Andrea Vecchi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Viral Escape ◽  
Cell Mediated Immunity ◽  
Structural Constraints ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Hla Class I Molecules

There is an urgent need for new generation anti-SARS-Cov-2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading. The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses. This analysis revealed variable levels of cross-neutralization capacity for presently available SARS-Cov-2 vaccines. Despite the dampened immune responses documented for some SARS-Cov-2 mutations, available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern (VoC). This may be attributed, at least in part, to cell-mediated immunity. Indeed, the widely multi-specific nature of CD8 T cell responses should allow to avoid VoC-mediated viral escape, because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co-existing CD8 epitopes. This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS-Cov-2 regions that cannot mutate without impairing SARS-Cov-2 functionality. Importantly, some of these conserved epitopes are degenerate, meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction. Based on these concepts, vaccination strategies aimed at potentiating the stimulatory effect on SARS-Cov-2-specific CD8 T cells should greatly enhance the efficacy of immunization against SARS-Cov-2 variants. Our review recollects, discusses and puts into a translational perspective all available experimental data supporting these “hot” concepts, with special emphasis on the structural constraints that limit SARS-CoV-2 S-protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next-generation, CD8 T-cell response-reinforced, COVID-19 vaccines.

scholarly journals Analysis of CD8+T cell response during the 2013–2016 Ebola epidemic in West Africa

2018 ◽  
Vol 115 (32) ◽  
pp. E7578-E7586 ◽  
Author(s):  
Saori Sakabe ◽  
Brian M. Sullivan ◽  
Jessica N. Hartnett ◽  
Refugio Robles-Sikisaka ◽  
Karthik Gangavarapu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
West Africa ◽  
Cell Response ◽  
Acute Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
T Cell Epitopes ◽  
Cell Responses

The recent Ebola epidemic exemplified the importance of understanding and controlling emerging infections. Despite the importance of T cells in clearing virus during acute infection, little is known about Ebola-specific CD8+T cell responses. We investigated immune responses of individuals infected with Ebola virus (EBOV) during the 2013–2016 West Africa epidemic in Sierra Leone, where the majority of the >28,000 EBOV disease (EVD) cases occurred. We examined T cell memory responses to seven of the eight Ebola proteins (GP, sGP, NP, VP24, VP30, VP35, and VP40) and associated HLA expression in survivors. Of the 30 subjects included in our analysis, CD8+T cells from 26 survivors responded to at least one EBOV antigen. A minority, 10 of 26 responders (38%), made CD8+T cell responses to the viral GP or sGP. In contrast, 25 of the 26 responders (96%) made response to viral NP, 77% to VP24 (20 of 26), 69% to VP40 (18 of 26), 42% (11 of 26) to VP35, with no response to VP30. Individuals making CD8+T cells to EBOV VP24, VP35, and VP40 also made CD8+T cells to NP, but rarely to GP. We identified 34 CD8+T cell epitopes for Ebola. Our data indicate the immunodominance of the EBOV NP-specific T cell response and suggest that its inclusion in a vaccine along with the EBOV GP would best mimic survivor responses and help boost cell-mediated immunity during vaccination.

scholarly journals Immunodominance in Mouse and Human CD4+ T-Cell Responses Specific for the Bordetella pertussis Virulence Factor P.69 Pertactin

2008 ◽  
Vol 77 (2) ◽  
pp. 896-903 ◽  
Author(s):  
Rachel M. Stenger ◽  
Martien C. M. Poelen ◽  
Ed E. Moret ◽  
Betsy Kuipers ◽  
Sven C. M. Bruijns ◽  
...  
Keyword(s):  
T Cell ◽  
Bordetella Pertussis ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Cell Immunity ◽  
Hla Dq ◽  
Natural Variants ◽  
Acellular Vaccines

ABSTRACT P.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis, Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+ T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restricted B. pertussis conserved CD4+ T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination and B. pertussis infection, and it was capable of evoking a Th1/Th17-type cytokine response. B. pertussis P.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present in Bordetella parapertussis and Bordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+ T cells in an HLA-DQ-restricted manner. During B. pertussis infection, the epitope was associated with a Th1-type CD4+ T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+ T-cell immunity after B. pertussis vaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance of B. pertussis-specific CD4+ T-cell mechanisms in preclinical and clinical vaccine studies.

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 Improved Immune Responses against Zika Virus after Sequential Dengue and Zika Virus Infection in Human

2018 ◽  
Author(s):  
Felix G. Delgado ◽  
Karina I. Torres ◽  
Jaime E. Castellanos ◽  
Consuelo Romero-Sánchez ◽  
Etienne Simon-Lorière ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Denv Infection ◽  
T Cell Response ◽  
Zikv Infection ◽  
Cell Responses ◽  
B Cell Responses

The high level of dengue virus (DENV) seroprevalence in areas where Zika virus (ZIKV) is circulating and the cross-reactivity between these two viruses have raised concerns on the risk of increased ZIKV disease severity for patients with a history of previous DENV infection. To determine the role of DENV pre-immunity in ZIKV infection, we analysed the T and B cell responses against ZIKV in donors with or without previous DENV infection. Using PBMCs from donors living in an endemic area in Colombia, we have identified, by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, most of the immunodominant ZIKV T-cell epitopes in the non-structural proteins NS1, NS3 and NS5. Analyses of the T and B-cell responses in the same donors revealed a stronger T-cell response against peptides conserved between DENV and ZIKV, with a higher level of ZIKV-neutralizing antibodies in DENV-immune donors, in comparison with DENV-naïve donors. Strikingly, the potential for antibody mediated enhancement of ZIKV infection was reduced in donors with sequential DENV and ZIKV infection in comparison with donors with DENV infection only. Altogether, these data suggest that individuals with DENV immunity present improved immune responses against ZIKV.

scholarly journals Potent HIV-1-Specific CD8 T Cell Responses Induced in Mice after Priming with a Multiepitopic DNA-TMEP and Boosting with the HIV Vaccine MVA-B

Viruses ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 424 ◽  
Author(s):  
Beatriz Perdiguero ◽  
Suresh C. Raman ◽  
Cristina Sánchez-Corzo ◽  
Carlos Oscar S. Sorzano ◽  
José Ramón Valverde ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Effective Vaccine ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Hiv 1

An effective vaccine against Human Immunodeficiency Virus (HIV) still remains the best solution to provide a sustainable control and/or eradication of the virus. We have previously generated the HIV-1 vaccine modified vaccinia virus Ankara (MVA)-B, which exhibited good immunogenicity profile in phase I prophylactic and therapeutic clinical trials, but was unable to prevent viral rebound after antiretroviral (ART) removal. To potentiate the immunogenicity of MVA-B, here we described the design and immune responses elicited in mice by a new T cell multi-epitopic B (TMEP-B) immunogen, vectored by DNA, when administered in homologous or heterologous prime/boost regimens in combination with MVA-B. The TMEP-B protein contained conserved regions from Gag, Pol, and Nef proteins including multiple CD4 and CD8 T cell epitopes functionally associated with HIV control. Heterologous DNA-TMEP/MVA-B regimen induced higher HIV-1-specific CD8 T cell responses with broader epitope recognition and higher polyfunctional profile than the homologous DNA-TMEP/DNA-TMEP or the heterologous DNA-GPN/MVA-B combinations. Moreover, higher HIV-1-specific CD4 and Tfh immune responses were also detected using this regimen. After MVA-B boost, the magnitude of the anti-VACV CD8 T cell response was significantly compromised in DNA-TMEP-primed animals. Our results revealed the immunological potential of DNA-TMEP prime/MVA-B boost regimen and supported the application of these combined vectors in HIV-1 prevention and/or therapy.

scholarly journals Sustained Specific and Cross-Reactive T Cell Responses to Zika and Dengue Virus NS3 in West Africa

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Bobby Brooke Herrera ◽  
Wen-Yang Tsai ◽  
Charlotte A. Chang ◽  
Donald J. Hamel ◽  
Wei-Kung Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Dengue Virus ◽  
Zika Virus ◽  
Cell Response ◽  
Vaccine Development ◽  
T Cell Responses ◽  
T Cell Response ◽  
Zikv Infection ◽  
Cell Responses

ABSTRACT Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3). Specifically, we found that T cell responses to NS3 protease are ZIKV and DENV specific, but responses to NS3 helicase are cross-reactive. Sequential sample analyses revealed immune responses sustained many years after infection. These results have important implications for African ZIKV/DENV vaccine development, as well as for potential flavivirus diagnostics based on T cell responses. IMPORTANCE The recent Zika virus (ZIKV) epidemic in Latin America and the associated congenital microcephaly and Guillain-Barré syndrome have raised questions as to why we have not recognized these distinct clinical diseases in Africa. The human immunologic response to ZIKV and related flaviviruses in Africa represents a research gap that may shed light on the mechanisms contributing to protection. The goal of our study was to develop an inexpensive assay to detect and characterize the T cell response to African ZIKV and DENV. Our data show long-term specific and cross-reactive human immune responses against African ZIKV and DENV, suggesting the usefulness of a diagnostic based on the T cell response. Additionally, we show that prior flavivirus exposure influences the magnitude of the T cell response. The identification of immune responses to African ZIKV and DENV is of relevance to vaccine development.

scholarly journals B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes.

1993 ◽  
Vol 177 (3) ◽  
pp. 679-690 ◽  
Author(s):  
F Ronchese ◽  
B Hausmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Scid Mice ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cell Responses

The ability of B cells or macrophages and dendritic cells (DC) to elicit class II-restricted T cell responses in vivo was compared using a mouse chimera model. Severe combined immunodeficient (SCID) mice (H-2d), reconstituted either with T or T+B lymphocytes from (H-2d x H-2b) donors, were immunized subcutaneously with protein antigen (Ag) to induce a class II-restricted T cell response. The frequency and major histocompatibility complex restriction of the resulting Ag-specific T cells were analyzed to establish whether B cells were necessary for the induction of class II-restricted T cell responses, and to determine the cell type on which priming had occurred. The results indicated that: (a) B cells are not necessary for the induction of a class II-restricted T cell response in vivo, as the frequencies of interleukin 2 (IL-2)- or IL-3-secreting T cells induced in the presence or absence of B cells were comparable. (b) Activation of naive T cells requires presentation of Ag on DC; Ag presented only on B cells is not sufficient to elicit a response. No H-2b-restricted, IL-3-secreting cells could in fact be detected in SCID mice reconstituted with naive (H-2d x H-2b) T cells and nonimmune or antigen-primed (H-2d x H-2b) B cells. (c) Previously primed T cells are able to be stimulated by Ag presented by both B cells and DC. H-2b-restricted, IL-3-secreting cells could in fact be readily demonstrated in SCID mice reconstituted with antigen-primed (H-2d x H-2b) T and B cells. Irrespective of whether the T cells were naive or previously activated, B cells were able to respond with an Ag-specific immunoglobulin G response, indicating that B cells were functional and able to present Ag in order to receive specific T cell help. Therefore, it appears that B cells are not necessary and do not participate in the initial priming of T cells; however, Ag presented by B cells can reactivate previously primed T cells. Taken together, these data indicate that during the course of an immune response Ag is first presented to naive T cells via DC, and only subsequently primed T cells can be stimulated by Ag presented by B cells.

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

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