Faculty Opinions recommendation of Cross-competition of CD8+ T cells shapes the immunodominance hierarchy during boost vaccination.

CD8+ T cell responses directed against multiple pathogen-derived epitopes are characterized by defined immunodominance hierarchy patterns. A possible explanation for this phenomenon is that CD8+ T cells of different specificities compete for access to epitopes on antigen-presenting cells, and that the outcome of this so-called cross-competition reflects the number of induced T cells. In our study using a vaccinia virus infection model, we found that T cell cross-competition is highly relevant during boost vaccination, thereby shaping the immunodominance hierarchy in the recall. We demonstrate that competition was of no importance during priming and was unaffected by the applied route of immunization. It strongly depended on the timing of viral antigen expression in infected APCs, and it was characterized by poor proliferation of T cells recognizing epitopes derived from late viral proteins. To our knowledge, this is the first demonstration of the functional importance of T cell cross-competition during a viral infection. Our findings provide a basis for novel strategies for how boost vaccination to defined antigens can be selectively improved. They give important new insights into the design of more efficient poxviral vectors for immunotherapy.

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Homologous Prime-Boost Vaccination with OVA Entrapped in Self-Adjuvanting Archaeosomes Induces High Numbers of OVA-Specific CD8+ T Cells that Protect Against Subcutaneous B16-OVA Melanoma

Vaccines ◽

10.3390/vaccines4040044 ◽

2016 ◽

Vol 4 (4) ◽

pp. 44 ◽

Cited By ~ 5

Author(s):

Felicity Stark ◽

Michael McCluskie ◽

Lakshmi Krishnan

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Boost Vaccination

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Antigen-dependent competition shapes the local repertoire of tissue-resident memory CD8+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20160888 ◽

2016 ◽

Vol 213 (13) ◽

pp. 3075-3086 ◽

Cited By ~ 55

Author(s):

Andreas Muschaweckh ◽

Veit R. Buchholz ◽

Anne Fellenzer ◽

Christian Hessel ◽

Paul-Albert König ◽

...

Keyword(s):

T Cells ◽

Cell Fate ◽

Cd8 T Cells ◽

Immune Surveillance ◽

Cell Formation ◽

Memory Cd8 T Cells ◽

Tcr Signals ◽

Necessary And Sufficient ◽

Resident Memory T Cells ◽

Cross Competition

Tissue-resident memory CD8+ T cells (TRM) constitute a major component of the immune-surveillance system in nonlymphoid organs. Local, noncognate factors are both necessary and sufficient to support the programming of TRM cell fate in tissue-infiltrating T cells. Recent evidence suggests that TCR signals received in infected nonlymphoid tissues additionally contribute to TRM cell formation. Here, we asked how antigen-dependent pathways influence the generation of skin-resident memory T cells that arise from a polyclonal repertoire of cells induced by infection with an antigenically complex virus and recombinant vaccine vector. We found that CD8+ T cells of different specificities underwent antigen-dependent competition in the infected tissue, which shaped the composition of the local pool of TRM cells. This local cross-competition was active for T cells recognizing antigens that are coexpressed by infected cells. In contrast, TRM cell development remained largely undisturbed by the presence of potential competitors when antigens expressed in the same tissue were segregated through infection with antigenically distinct viral quasispecies. Functionally, local cross-competition might serve as a gatekeeping mechanism to regulate access to the resident memory niche and to fine-tune the local repertoire of antiviral TRM cells.

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In vivo CTL Activity Induced by Prime-boost Vaccination using Recombinant Vaccinia Virus and DNA Vaccine Expressing Epitope Specific for CD8+ T Cells

Journal of Bacteriology and Virology ◽

10.4167/jbv.2007.37.1.1 ◽

2007 ◽

Vol 37 (1) ◽

pp. 1

Author(s):

Young Woo Han ◽

Seong Ok Park ◽

A Rum Kim ◽

Abi G. Aleyas ◽

Junu A. George ◽

...

Keyword(s):

T Cells ◽

Vaccinia Virus ◽

Dna Vaccine ◽

Cd8 T Cells ◽

Recombinant Vaccinia Virus ◽

Recombinant Vaccinia ◽

Boost Vaccination ◽

Ctl Activity

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Airway delivery of both a BCG prime and adenoviral boost drives CD4 and CD8 T cells into the lung tissue parenchyma

Scientific Reports ◽

10.1038/s41598-020-75734-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Daryan A. Kaveh ◽

M. Carmen Garcia-Pelayo ◽

Naomi C. Bull ◽

Pedro J. Sanchez-Cordon ◽

John Spiropoulos ◽

...

Keyword(s):

T Cells ◽

Lung Tissue ◽

Cd8 T Cells ◽

Murine Model ◽

Vaccine Development ◽

Lung Parenchyma ◽

Boost Vaccination ◽

Parenteral Delivery ◽

Promising Strategy ◽

Intravascular Staining

Abstract Heterologous BCG prime-boost regimens represent a promising strategy for an urgently required improved tuberculosis vaccine. Identifying the mechanisms which underpin the enhanced protection induced by such strategies is one key aim which would significantly accelerate rational vaccine development. Experimentally, airway vaccination induces greater efficacy than parenteral delivery; in both conventional vaccination and heterologous boosting of parenteral BCG immunisation. However, the effect of delivering both the component prime and boost immunisations via the airway is not well known. Here we investigate delivery of both the BCG prime and adenovirus boost vaccination via the airway in a murine model, and demonstrate this approach may be able to improve the protective outcome over parenteral prime/airway boost. Intravascular staining of T cells in the lung revealed that the airway prime regimen induced more antigen-specific multifunctional CD4 and CD8 T cells to the lung parenchyma prior to challenge and indicated the route of both prime and boost to be critical to the location of induced resident T cells in the lung. Further, in the absence of a defined phenotype of vaccine-induced protection to tuberculosis; the magnitude and phenotype of vaccine-specific T cells in the parenchyma of the lung may provide insights into potential correlates of immunity.

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Rapid and stable mobilization of fully functional spike-specific CD8+ T cells preceding a mature humoral response after SARS-CoV-2 mRNA vaccination

10.21203/rs.3.rs-505193/v1 ◽

2021 ◽

Author(s):

Robert Thimme ◽

Valerie Oberhardt ◽

Hendrik Luxenburger ◽

Janine Kemming ◽

Isabel Schulien ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Adaptive Immunity ◽

Cd8 T Cells ◽

Neutralizing Antibodies ◽

Memory T Cells ◽

Natural Infection ◽

Cd8 T Cell ◽

Effector Memory ◽

Boost Vaccination

Abstract SARS-CoV-2 spike mRNA vaccines mediate protection from severe disease as early as 10 days post prime vaccination, when specific antibodies are hardly detectable and still lack neutralizing activity. Vaccine-induced T cells, especially CD8+ T cells, may thus be the main mediators of protection at this early stage. The details of antigen-specific CD8+ T cell induction after prime/boost vaccination, their comparison to naturally induced CD8+ T cell responses and their association with other arms of vaccine-induced adaptive immunity remain, however, incompletely understood. Here, we show on a single epitope level that both, a stable memory precursor pool of spike-specific CD8+ T cells and fully functional spike-specific effector CD8+ T cell populations, are vigorously mobilized as early as one week after prime vaccination when CD4+ T cell and spike-specific antibody responses are still weak and neutralizing antibodies are lacking. Boost vaccination after 3 weeks induced a full-fledged recall expansion generating highly differentiated CD8+ effector T cells, however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared to natural infection, vaccine-induced early memory T cells exhibited similar frequencies and functional capacities but a different subset distribution dominated by effector memory T cells at the expense of self-renewing and multipotent central memory T cells. Our results indicate that spike-specific CD8+ T cells may represent the major correlate of early protection after SARS-CoV-2 mRNA/bnt162b2 prime vaccination that precede other effector arms of vaccine-induced adaptive immunity and are stably maintained after boost vaccination.

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Heterologous Prime-Boost Vaccination with a Peptide-Based Vaccine and Viral Vector Reshapes Dendritic Cell, CD4+ and CD8+ T Cell Phenotypes to Improve the Antitumor Therapeutic Effect

Cancers ◽

10.3390/cancers13236107 ◽

2021 ◽

Vol 13 (23) ◽

pp. 6107

Author(s):

Tamara Hofer ◽

Matteo Rossi ◽

Susanna Carboni ◽

Wilma Di Berardino Besson ◽

Dorothee von Laer ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Lymph Nodes ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Viral Vector ◽

Mouse Tumor ◽

Protein Vaccine ◽

Boost Vaccination ◽

Draining Lymph Nodes

Heterologous prime-boost settings with a protein vaccine and the viral vector vesicular stomatitis virus, both expressing tumor-associated antigens (KISIMA-TAA and VSV-GP-TAA), have been previously shown to generate potent antitumor immunity. In the cold TC-1 model (HPV antigen) and the immune-infiltrate MC-38 model (Adpgk, Reps1 and Rpl18 neo-antigens), we further investigated pivotal immune cells that educate CD8+ T cells. Heterologous prime-boost vaccination induced a superior antitumor response characterized by the increase in number and functionality of antigen-specific CD8+ T cells, recruitment of cross-presenting dendritic cells, and polarization of CD4+ T cells towards an antitumor Th1 phenotype within the tumor and tumor-draining lymph nodes, turning the cold TC-1 tumor into a hot, inflamed tumor. In the inflamed MC-38 tumor model, treatment combination markedly prolonged the overall survival of mice. Treatment with multi-epitope vaccines also induced high frequencies of multiple antigen specificities in the periphery and in the tumor. Prime-boost treatment reduced tumor-infiltrating regulatory CD4+ T cells whilst increasing cross-presenting dendritic cells in tumor-draining lymph nodes. In conclusion, heterologous prime-boost vaccination possesses the ability to induce a potent anti-tumor response in both immune-excluded and immune-infiltrated mouse tumor models. Additionally, this study highlights the design of a multi-epitope vaccine for cancer immunotherapy.

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Combined HDAC and BET inhibition to enhance cancer vaccine-elicited T-cell responses.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14632 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14632-e14632

Author(s):

Alexander Badamchi-Zadeh ◽

Kelly Dare Moynihan ◽

Nicholas M Provine ◽

Rafael Larocca ◽

Darrell J Irvine ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Ductal Adenocarcinoma ◽

Cell Responses ◽

Boost Vaccination ◽

Immunological Mechanisms ◽

Ifn Γ

e14632 Background: The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromo and extra terminal (BET) family have recently shown therapeutic efficacy against pancreatic ductal adenocarcinoma, melanoma and lymphoma cancers in murine studies. However, in these studies the role of the immune system in therapeutically controlling these cancers was not explored. Methods: We sought to investigate the effect of the HDAC inhibitor romidepsin (RMD) and the BET inhibitor I-BET151, both singly and in combination, on vaccine elicited immune responses. C57Bl/6 mice were immunized with differing vaccines (Adenoviral, protein) in prime-boost regimens, under treatment with RMD, I-BET151, or RMD+I-BET151. Results: The combination RMD+I-BET151, administered during Adenoviral prime-boost vaccination, resulted in the significant increase in the frequency and number of antigen-specific CD8 T cells. RMD+I-BET151 treatment affected vaccine-elicited secondary T cell responses, significantly increasing the frequency of IFN-γ+ splenic CD8 T cells and maintaining their dual IFN-γ+TNFa+ polyfunctionality. These CD8 T cells maintained their protective ability against Listeria monocytogenes, and protected against B16-OVA challenge. The significant augmentation of vaccine elicited CD8 T cell responses under RMD+I-BET151 treatment was additionally observed following protein (OVA+CpG) prime-boost vaccination, resulting in greater protection against B16-OVA challenge and enhanced survival. T-regulatory cell (FoxP3+CD4+) frequency and total CD4 and CD8 cell numbers remained unaltered following RMD+I-BET151 treatment. Conclusions: Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8 T cell responses following immunization by multiple vaccine platforms, and enhanced protection against B16-OVA challenges. We are currently assessing immunological mechanisms of action for this combined HDAC and BET inhibition.

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