Antigen-Specific T-Cell Responses to a Recombinant Fowlpox Virus Are Dependent on MyD88 and Interleukin-18 and Independent of Toll-Like Receptor 7 (TLR7)- and TLR9-Mediated Innate Immune Recognition

Despite lack of tumor control in many models, spontaneous T cell priming occurs frequently in response to a growing tumor. However, the innate immune mechanisms that promote natural antitumor T cell responses are undefined. In human metastatic melanoma, there was a correlation between a type I interferon (IFN) transcriptional profile and T cell markers in metastatic tumor tissue. In mice, IFN-β was produced by CD11c+ cells after tumor implantation, and tumor-induced T cell priming was defective in mice lacking IFN-α/βR or Stat1. IFN signaling was required in the hematopoietic compartment at the level of host antigen-presenting cells, and selectively for intratumoral accumulation of CD8α+ dendritic cells, which were demonstrated to be essential using Batf3−/− mice. Thus, host type I IFNs are critical for the innate immune recognition of a growing tumor through signaling on CD8α+ DCs.

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Enhanced T-Cell Immunogenicity and Protective Efficacy of a Human Immunodeficiency Virus Type 1 Vaccine Regimen Consisting of Consecutive Priming with DNA and Boosting with Recombinant Fowlpox Virus

Journal of Virology ◽

10.1128/jvi.72.12.10180-10188.1998 ◽

1998 ◽

Vol 72 (12) ◽

pp. 10180-10188 ◽

Cited By ~ 249

Author(s):

Stephen J. Kent ◽

Anne Zhao ◽

Susan J. Best ◽

Jenalle D. Chandler ◽

David B. Boyle ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Responses ◽

Fowlpox Virus ◽

Vaccine Regimen ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Recombinant Fowlpox Virus ◽

Hiv 1

ABSTRACT The induction of human immunodeficiency virus (HIV)-specific T-cell responses is widely seen as critical to the development of effective immunity to HIV type 1 (HIV-1). Plasmid DNA and recombinant fowlpox virus (rFPV) vaccines are among the most promising safe HIV-1 vaccine candidates. However, the immunity induced by either vaccine alone may be insufficient to provide durable protection against HIV-1 infection. We evaluated a consecutive immunization strategy involving priming with DNA and boosting with rFPV vaccines encoding common HIV-1 antigens. In mice, this approach induced greater HIV-1-specific immunity than either vector alone and protected mice from challenge with a recombinant vaccinia virus expressing HIV-1 antigens. In macaques, a dramatic boosting effect on DNA vaccine-primed HIV-1-specific helper and cytotoxic T-lymphocyte responses, but a decline in HIV-1 antibody titers, was observed following rFPV immunization. The vaccine regimen protected macaques from an intravenous HIV-1 challenge, with the resistance most likely mediated by T-cell responses. These studies suggest a safe strategy for the enhanced generation of T-cell-mediated protective immunity to HIV-1.

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The Innate Immune Sensor NLRC3 Acts as a Rheostat that Fine-Tunes T Cell Responses in Infection and Autoimmunity

Immunity ◽

10.1016/j.immuni.2018.10.008 ◽

2018 ◽

Vol 49 (6) ◽

pp. 1049-1061.e6 ◽

Cited By ~ 15

Author(s):

Toru Uchimura ◽

Yoshitaka Oyama ◽

Meng Deng ◽

Haitao Guo ◽

Justin E. Wilson ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Innate Immune ◽

Cell Responses

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A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0406740101 ◽

2004 ◽

Vol 101 (43) ◽

pp. 15440-15445 ◽

Cited By ~ 181

Author(s):

D. C. Jackson ◽

Y. F. Lau ◽

T. Le ◽

A. Suhrbier ◽

G. Deliyannis ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Toll Like Receptor ◽

Generic Structure ◽

Cell Responses ◽

Toll Like Receptor 2 ◽

Cytotoxic T Cell Responses

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Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses

Vaccines ◽

10.3390/vaccines8010004 ◽

2019 ◽

Vol 8 (1) ◽

pp. 4 ◽

Cited By ~ 9

Author(s):

Muktha S. Natrajan ◽

Nadine Rouphael ◽

Lilin Lai ◽

Dmitri Kazmin ◽

Travis L. Jensen ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Innate Immune ◽

Antibody Responses ◽

Cytokine Signaling ◽

Cell Responses ◽

Viral Vaccine ◽

Tularemia Vaccine

Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized viral vaccine immune responses. Methods: Microarray analyses were performed on human peripheral blood mononuclear cells (PBMCs) to determine changes in transcriptional activity that correlated with changes detected by cellular phenotyping, cytokine signaling, and serological assays. Transcriptional profiles after tularemia vaccination were compared with yellow fever [YF-17D], inactivated [TIV], and live attenuated [LAIV] influenza. Results: Tularemia vaccine lots produced strong innate immune responses by Day 2 after vaccination, with an increase in monocytes, NK cells, and cytokine signaling. T cell responses peaked at Day 14. Changes in gene expression, including upregulation of STAT1, GBP1, and IFIT2, predicted tularemia-specific antibody responses. Changes in CCL20 expression positively correlated with peak CD8+ T cell responses, but negatively correlated with peak CD4+ T cell activation. Tularemia vaccines elicited gene expression signatures similar to other replicating vaccines, inducing early upregulation of interferon-inducible genes. Conclusions: A systems vaccinology approach identified that tularemia vaccines induce a strong innate immune response early after vaccination, similar to the response seen after well-studied viral vaccines, and produce unique transcriptional signatures that are strongly correlated to the induction of T cell and antibody responses.

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2729. mRNA Vaccines Encoding Conserved Influenza Antigens Induce Robust and Durable Immunity in Rhesus Macaques

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2407 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S961-S961

Author(s):

Jessica Flynn ◽

Kara Cox ◽

Sinoeun Touch ◽

Yangsi Ou ◽

Teresa Weber ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Rhesus Macaques ◽

Vaccine Dose ◽

T Cell Responses ◽

Immune Recognition ◽

Serum Antibodies ◽

Ifn Gamma ◽

Cell Responses ◽

Lipid Nanoparticle

Abstract Background In response to immune pressure, influenza virus evolves, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response that can recognize multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the immunogenicity of mRNA vaccines encoding the stem domain of hemagglutinin (HA) or nucleoprotein (NP) in nonhuman primates (NHPs). Methods Rhesus macaques were immunized three times intramuscularly, at 28 day intervals, with lipid nanoparticle-encapsulated mRNA encoding either HA stem (Yassine et al, 2015) or NP. Serum and PBMCs were collected up to 14 or 24 weeks, respectively, after the last vaccination. The magnitude and durability of humoral and cell-mediated immunity were evaluated. ELISA, competition ELISA, an in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) reporter bioassay, and microneutralization assays were used to characterize serum immune responses. Intracellular cytokine staining (IFN-gamma and IL-2) was used to assess antigen-specific T-cell responses. Results HA stem-immunized NHPs developed a robust anti-stem binding titer after a single vaccine dose, and after two doses, serum antibodies recognized several antigenically distinct Group 1 HA proteins. This broad antibody response persisted for at least 14 weeks post-dose 3 (PD3). Serum antibodies showed ADCC activity and competed with a well-characterized broadly neutralizing antibody, CR9114, for binding to HA stem; however, the polyclonal serum had only minimal activity against a panel of H1N1 viruses in a microneutralization assay. HA-specific CD4+ T-cell responses were detectable PD3. A robust antibody binding response was also detected in NP-vaccinated NHPs, and titers remained high for at least 14 weeks PD3. Additionally, these animals developed robust NP-specific T-cell responses that persisted for at least 24 weeks PD3. On average, 0.5% of CD4+ and 4% of CD8+ T cells produced IFN-gamma in response to NP peptide stimulation at the peak of the response, 2 weeks after the last vaccine dose was administered. Conclusion Lipid nanoparticle-encapsulated mRNA vaccines encoding conserved influenza antigens induce a robust and durable immune response in NHPs. Disclosures All authors: No reported disclosures.

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Timing of Toll-Like Receptor 9 Agonist Administration in Pneumococcal Vaccination Impacts Both Humoral and Cellular Immune Responses as Well as Nasopharyngeal Colonization in Mice

Infection and Immunity ◽

10.1128/iai.00079-12 ◽

2012 ◽

Vol 80 (5) ◽

pp. 1744-1752 ◽

Cited By ~ 4

Author(s):

Katrine M. Jensen ◽

Jesper Melchjorsen ◽

Frederik Dagnaes-Hansen ◽

Uffe B. S. Sørensen ◽

Rune R. Laursen ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Conjugate Vaccine ◽

Interleukin 2 ◽

T Cell Responses ◽

Simultaneous Administration ◽

Toll Like Receptor ◽

Wild Type ◽

Content Type ◽

Cell Responses

ABSTRACTSynthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs, CpG ODN, are Toll-like receptor 9 agonists (TLR9a), which have been used as adjuvants in pneumococcal vaccines to improve antibody responses in immunodeficient patients. Here, we examined whether the coadministration of TLR9a with pneumococcal CRM197-conjugate vaccine enhances protection against pneumococcal colonization, the levels of antipolysaccharide antibodies, and the CD4+T-cell responses. Wild-type BALB/c mice and B-cell-deficient BALB/c Igh-Jtm1Dhumice were immunized twice with the following: (i) PCV alone; (ii) simultaneous PCV and TLR9a; (iii) PCV and then TLR9a, after a 48-h delay; (iv) TLR9a alone; and (v) phosphate-buffered saline. Nasopharyngeal protection, serum antibodies, CD4+T-cell responses, and clearance of bacteremia after intraperitoneal challenge withStreptococcus pneumoniae6B were evaluated. We found decreased nasopharyngeal protection againstS. pneumoniae6B colonization after simultaneous immunization with PCV and TLR9a compared to immunization with PCV alone in wild-type BALB/c mice (P= 0.037). A similar trend was observed in B-cell-deficient BALB/c Igh-Jtm1Dhumice. Simultaneous administration did not enhance antibody levels and lowered the CRM197-specific cytokine release of gamma interferon, interleukin-2 (IL-2), IL-5 and IL-13. Immunization with PCV and then TLR9a, after a 48-h delay, significantly improved nasopharyngeal protection compared to simultaneous administration (P= 0.011). Furthermore, delaying TLR9a delivery increased antibody titers compared to both simultaneous administration (P= 0.001) and PCV immunization alone (P= 0.026). In conclusion, the immunological and clinical impact of adjuvanting a pneumococcal conjugate vaccine (Prevnar; Pfizer) with a TLR9a is highly depended on timing of the adjuvant administration. Thus, careful timing of adjuvant administration may improve novel vaccine formulations.

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Bacterial antigens elicit T cell responses via adaptive and transitional immune recognition

Current Opinion in Microbiology ◽

10.1016/s1369-5274(00)00201-0 ◽

2001 ◽

Vol 4 (3) ◽

pp. 267-273 ◽

Cited By ~ 6

Author(s):

Brad T Cookson ◽

Lisa A Cummings ◽

Sara L Rassoulian Barrett

Keyword(s):

T Cell ◽

T Cell Responses ◽

Immune Recognition ◽

Cell Responses ◽

Bacterial Antigens

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The Effects of Trained Innate Immunity on T Cell Responses; Clinical Implications and Knowledge Gaps for Future Research

Frontiers in Immunology ◽

10.3389/fimmu.2021.706583 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dearbhla M. Murphy ◽

Kingston H. G. Mills ◽

Sharee A. Basdeo

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cells ◽

T Cell Responses ◽

Innate Immune ◽

Metabolic Reprogramming ◽

Innate Immune Cells ◽

Peripheral Tissues ◽

Trained Immunity ◽

Cell Responses

The burgeoning field of innate immune training, also called trained immunity, has given immunologists new insights into the role of innate responses in protection against infection and in modulating inflammation. Moreover, it has led to a paradigm shift in the way we think about immune memory and the interplay between innate and adaptive immune systems in conferring immunity against pathogens. Trained immunity is the term used to describe the medium-term epigenetic and metabolic reprogramming of innate immune cells in peripheral tissues or in the bone marrow stem cell niche. It is elicited by an initial challenge, followed by a significant period of rest that results in an altered response to a subsequent, unrelated challenge. Trained immunity can be associated with increased production of proinflammatory mediators, such as IL-1β, TNF and IL-6, and increased expression of markers on innate immune cells associated with antigen presentation to T cells. The microenvironment created by trained innate immune cells during the secondary challenge may have profound effects on T cell responses, such as altering the differentiation, polarisation and function of T cell subtypes, including Th17 cells. In addition, the Th1 cytokine IFN-γ plays a critical role in establishing trained immunity. In this review, we discuss the evidence that trained immunity impacts on or can be impacted by T cells. Understanding the interplay between innate immune training and how it effects adaptive immunity will give insights into how this phenomenon may affect the development or progression of disease and how it could be exploited for therapeutic interventions or to enhance vaccine efficacy.

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