Activation of influenza virus–specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons (IFNs) upon exposure to enveloped viruses. However, their role in adaptive immune responses, such as the initiation of antiviral T-cell responses, is not known. In this study, we examined interactions between blood pDCs and influenza virus with special attention to the capacity of pDCs to activate influenza-specific T cells. pDCs were compared with CD11c+ DCs, the most potent antigen-presenting cells (APCs), for their capacity to activate T-cell responses. We found that like CD11c+ DCs, pDCs mature following exposure to influenza virus, express CCR7, and produce proinflammatory chemokines, but differ in that they produce type I IFN and are resistant to the cytopathic effect of the infection. After influenza virus exposure, both DC types exhibited an equivalent efficiency to expand anti–influenza virus cytotoxic T lymphocytes (CTLs) and T helper 1 (TH1) CD4+ T cells. Our results pinpoint a new role of pDCs in the induction of antiviral T-cell responses and suggest that these DCs play a prominent role in the adaptive immune response against viruses.

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T Cell Responses in Patients Vaccinated with Telomerase (hTERT)-mRNA Transfected Dendritic Cells.

Blood ◽

10.1182/blood.v114.22.373.373 ◽

2009 ◽

Vol 114 (22) ◽

pp. 373-373

Author(s):

Else Marit Inderberg Suso ◽

Anne-Marie Rasmussen ◽

Steinar Aamdal ◽

Svein Dueland ◽

Gustav Gaudernack ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Patients ◽

Cd8 T Cells ◽

Stable Disease ◽

T Cell Responses ◽

Htert Mrna ◽

Cell Responses

Abstract Abstract 373 Two cancer patients were vaccinated with dendritic cells (DC) loaded with telomerase (hTERT) mRNA to investigate the safety, tolerability and immunological response to vaccination prior to the start of a new phase I/II clinical trial. Following written informed consent one primary lung adenocarcinoma with metastasis and one patient with a relapsed pancreatic ductal type of adenocarcinoma, were treated with autologus monocyte-derived DC transfected with mRNA encoding hTERT. The patients first received four weekly injections administered intradermally followed by monthly booster injections. Peripheral blood mononuclear cells (PBMC) at each vaccination time point were tested in vitro with transfected DC and a panel of 24 overlapping hTERT peptides. In addition, hTERT-specific CD8+ T cells were monitored by pentamer staining. The treatment was well tolerated with minor side effects. Immune responses against telomerase-transfected DC and some of the overlapping hTERT peptides were detected in both patients. We also detected hTERT-specific CD8+ T cells in both patients by pentamer staining in post-vaccination samples. The lung cancer patients obtained a stable disease that lasted 18 months while the patient with pancreas cancer who started the DC vaccination in July 2007 following palliative chemotherapy, still is in stable disease by continuously boost vaccination. T-cell responses against telomerase epitopes have also been identified in both non-vaccinated cancer patients and cancer patients previously vaccinated with telomerase peptide. Since patients with these findings often show extraordinary clinical courses of their disease we hypothesize that it exists a high degree of immunogenicity and HLA promiscuity for some telomerase epitopes. In this study we have shown that vaccination with hTERT-mRNA transfected DC is safe and able to induce robust immune responses to several telomerase T-cell epitopes both in CD4+ and CD8+ T cells. This opens up the possibility for a broad clinical application of mRNA hTERT DC vaccines. Furthermore, responding T cells identified in these patients are strong candidates for T-cell receptor cloning and the receptors identified can thereafter be transferred into T cells creating the next generation of immuno-gene therapy with retargeted T cells. Disclosures: No relevant conflicts of interest to declare.

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Interleukin-12p70 Expression by Dendritic Cells of HIV-1-Infected Patients Fails to Stimulategag-Specific Immune Responses

Clinical and Developmental Immunology ◽

10.1155/2012/184979 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Ellen Van Gulck ◽

Nathalie Cools ◽

Derek Atkinson ◽

Lotte Bracke ◽

Katleen Vereecken ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Hiv Replication ◽

Cell Responses ◽

Antigen Presenting ◽

Hiv 1 ◽

Unique Capability

A variety of immune-based therapies has been developed in order to boost or induce protective CD8+T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2gagmRNA enhances their capacity to induce HIVgag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2gag-expressing DCs to expand functional HIV-specific CD8+T cells. However, although most of the patients had detectablegag-specific CD8+T cell responses, no significant differences in the level of expansion of functional CD8+T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

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Innate immunity defines the capacity of antiviral T cells to limit persistent infection

Journal of Experimental Medicine ◽

10.1084/jem.20091193 ◽

2010 ◽

Vol 207 (6) ◽

pp. 1333-1343 ◽

Cited By ~ 157

Author(s):

Daniel M. Andrews ◽

Marie J. Estcourt ◽

Christopher E. Andoniou ◽

Matthew E. Wikstrom ◽

Andrea Khong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Nk Cells ◽

Viral Persistence ◽

T Cell Responses ◽

Cell Responses ◽

Adaptive Immune ◽

Acquired Immune Responses ◽

Antigen Presenting

Effective immunity requires the coordinated activation of innate and adaptive immune responses. Natural killer (NK) cells are central innate immune effectors, but can also affect the generation of acquired immune responses to viruses and malignancies. How NK cells influence the efficacy of adaptive immunity, however, is poorly understood. Here, we show that NK cells negatively regulate the duration and effectiveness of virus-specific CD4+ and CD8+ T cell responses by limiting exposure of T cells to infected antigen-presenting cells. This impacts the quality of T cell responses and the ability to limit viral persistence. Our studies provide unexpected insights into novel interplays between innate and adaptive immune effectors, and define the critical requirements for efficient control of viral persistence.

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Systems Immunology Analyses Following Porcine Respiratory and Reproductive Syndrome Virus Infection and Vaccination

Frontiers in Immunology ◽

10.3389/fimmu.2021.779747 ◽

2021 ◽

Vol 12 ◽

Author(s):

Loïc Vivien Bocard ◽

Andrew Robert Kick ◽

Corinne Hug ◽

Heidi Erika Lisa Lischer ◽

Tobias Käser ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cd8 T Cell ◽

Innate Immune ◽

Type I ◽

Adaptive Immune Responses ◽

Cell Responses ◽

Adaptive Immune

This study was initiated to better understand the nature of innate immune responses and the relatively weak and delayed immune response against porcine reproductive and respiratory syndrome virus (PRRSV). Following modified live virus (MLV) vaccination or infection with two PRRSV-2 strains, we analyzed the transcriptome of peripheral blood mononuclear cells collected before and at three and seven days after vaccination or infection. We used blood transcriptional modules (BTMs)-based gene set enrichment analyses. BTMs related to innate immune processes were upregulated by PRRSV-2 strains but downregulated by MLV. In contrast, BTMs related to adaptive immune responses, in particular T cells and cell cycle, were downregulated by PRRSV-2 but upregulated by MLV. In addition, we found differences between the PRRSV strains. Only the more virulent strain induced a strong platelet activation, dendritic cell activation, interferon type I and plasma cell responses. We also calculated the correlations of BTM with the neutralizing antibody and the T-cell responses. Early downregulation (day 0–3) of dendritic cell and B-cell BTM correlated to both CD4 and CD8 T-cell responses. Furthermore, a late (day 3–7) upregulation of interferon type I modules strongly correlated to helper and regulatory T-cell responses, while inflammatory BTM upregulation correlated more to CD8 T-cell responses. BTM related to T cells had positive correlations at three days but negative associations at seven days post-infection. Taken together, this work contributes to resolve the complexity of the innate and adaptive immune responses against PRRSV and indicates a fundamentally different immune response to the less immunogenic MLV compared to field strains which induced robust adaptive immune responses. The identified correlates of T-cell responses will facilitate a rational approach to improve the immunogenicity of MLV.

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Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.688347 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yana Hackler ◽

Frank Siebenhaar ◽

Max Löhning ◽

Marcus Maurer ◽

Melba Muñoz

Keyword(s):

T Cells ◽

T Cell ◽

Mast Cells ◽

Immune Responses ◽

Cytokine Production ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Deficient Mice ◽

Lcmv Infection

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

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Immunization with host-type CD8α+ dendritic cells reduces experimental acute GVHD in an IL-10–dependent manner

Blood ◽

10.1182/blood-2009-06-229708 ◽

2010 ◽

Vol 115 (3) ◽

pp. 724-735 ◽

Cited By ~ 20

Author(s):

Tomomi Toubai ◽

Chelsea Malter ◽

Isao Tawara ◽

Chen Liu ◽

Evelyn Nieves ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Major Histocompatibility Complex ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Class Ii ◽

Cell Responses ◽

Histocompatibility Complex

Abstract Little is known about the role of active immunization in suppressing undesirable immune responses. Because CD8α+ dendritic cells (DCs) suppress certain immune responses, we tested the hypothesis that immunization of donors with host-derived CD8α+ DCs will reduce host-specific donor T-cell responses. BALB/c T cells from the animals that were immunized with B6 CD8α+ DCs demonstrated, in vitro and in vivo, significantly reduced proliferation and secretion of inflammatory cytokines but showed enhanced secretion of interleukin-10 (IL-10). The responses against third-party and model antigens were preserved demonstrating antigen specificity. The in vivo relevance was further demonstrated by the reduction on graft-versus-host disease (GVHD) in both a major histocompatibility complex–mismatched clinically relevant BALB/c → B6 model and major histocompatibility complex–matched, minor-mismatched C3H.SW → B6 model of GVHD. Immunization of the donors that were deficient in IL-10 (IL-10−/−) or with CD8α+ DCs from B6 class II (class II−/−) failed to reduce T-cell responses, demonstrating (1) a critical role for secretion of IL-10 by donor T cells and (2) a direct contact between the T cells and the CD8α+ DCs. Together, these data may represent a novel strategy for reducing GVHD and suggest a broad counterintuitive role for vaccination strategies in mitigating undesirable immune responses in an antigen-specific manner.

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P126 Defective type I IFNS production by plasmacytoid dendritic cells impairs T cell responses and virus control in early life

Cytokine ◽

10.1016/j.cyto.2012.06.218 ◽

2012 ◽

Vol 59 (3) ◽

pp. 559-560

Author(s):

E. Belnoue ◽

P. Fontannaz ◽

A.-F. Rochat ◽

P.-H. Lambert ◽

D. Pinschewer ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Early Life ◽

T Cell Responses ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Virus Control ◽

Cell Responses ◽

Type I Ifns

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Functional Limitations of Plasmacytoid Dendritic Cells Limit Type I Interferon, T Cell Responses and Virus Control in Early Life

PLoS ONE ◽

10.1371/journal.pone.0085302 ◽

2013 ◽

Vol 8 (12) ◽

pp. e85302 ◽

Cited By ~ 12

Author(s):

Elodie Belnoue ◽

Paola Fontannaz ◽

Anne-Françoise Rochat ◽

Chantal Tougne ◽

Andreas Bergthaler ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Early Life ◽

Type I Interferon ◽

Functional Limitations ◽

T Cell Responses ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Virus Control ◽

Cell Responses

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CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01

Frontiers in Immunology ◽

10.3389/fimmu.2020.606805 ◽

2021 ◽

Vol 11 ◽

Author(s):

Cedric Bosteels ◽

Kaat Fierens ◽

Sofie De Prijck ◽

Justine Van Moorleghem ◽

Manon Vanheerswynghels ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Lymph Node ◽

T Cell ◽

Adaptive Immunity ◽

T Cell Responses ◽

Cell Responses ◽

Adaptive Immune ◽

Adjuvant System ◽

Draining Lymph Node

The Adjuvant System AS01 contains monophosphoryl lipid A (MPL) and the saponin QS-21 in a liposomal formulation. AS01 is included in recently developed vaccines against malaria and varicella zoster virus. Like for many other adjuvants, induction of adaptive immunity by AS01 is highly dependent on the ability to recruit and activate dendritic cells (DCs) that migrate to the draining lymph node for T and B cell stimulation. The objective of this study was to more precisely address the contribution of the different conventional (cDC) and monocyte-derived DC (MC) subsets in the orchestration of the adaptive immune response after immunization with AS01 adjuvanted vaccine. The combination of MPL and QS-21 in AS01 induced strong recruitment of CD26+XCR1+ cDC1s, CD26+CD172+ cDC2s and a recently defined CCR2-dependent CD64-expressing inflammatory cDC2 (inf-cDC2) subset to the draining lymph node compared to antigen alone, while CD26-CD64+CD88+ MCs were barely detectable. At 24 h post-vaccination, cDC2s and inf-cDC2s were superior amongst the different subsets in priming antigen-specific CD4+ T cells, while simultaneously presenting antigen to CD8+ T cells. Diphtheria toxin (DT) mediated depletion of all DCs prior to vaccination completely abolished adaptive immune responses, while depletion 24 h after vaccination mainly affected CD8+ T cell responses. Vaccinated mice lacking Flt3 or the chemokine receptor CCR2 showed a marked deficit in inf-cDC2 recruitment and failed to raise proper antibody and T cell responses. Thus, the adjuvant activity of AS01 is associated with the potent activation of subsets of cDC2s, including the newly described inf-cDC2s.

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Modulation of Dendritic Cells by Microbiota Extracellular Vesicles Influences the Cytokine Profile and Exosome Cargo

Nutrients ◽

10.3390/nu14020344 ◽

2022 ◽

Vol 14 (2) ◽

pp. 344

Author(s):

Natalia Diaz-Garrido ◽

Josefa Badia ◽

Laura Baldomà

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Extracellular Vesicles ◽

T Cell Activation ◽

T Cell Responses ◽

E Coli ◽

Cell Responses ◽

Secreted Factors

Gut bacteria release extracellular vesicles (BEVs) as an intercellular communication mechanism that primes the host innate immune system. BEVs from E. coli activate dendritic cells (DCs) and subsequent T-cell responses in a strain-specific manner. The specific immunomodulatory effects were, in part, mediated by differential regulation of miRNAs. This study aimed to deepen understanding of the mechanisms of BEVs to drive specific immune responses by analyzing their impact on DC-secreted cytokines and exosomes. DCs were challenged with BEVs from probiotic and commensal E. coli strains. The ability of DC-secreted factors to activate T-cell responses was assessed by cytokine quantification in indirect DCs/naïve CD4+ T-cells co-cultures on Transwell supports. DC-exosomes were characterized in terms of costimulatory molecules and miRNAs cargo. In the absence of direct cellular contacts, DC-secreted factors triggered secretion of effector cytokines by T-cells with the same trend as direct DC/T-cell co-cultures. The main differences between the strains influenced the production of Th1- and Treg-specific cytokines. Exosomes released by BEV-activated DCs were enriched in surface proteins involved in antigen presentation and T-cell activation, but differed in the content of immune-related miRNA, depending on the origin of the BEVs. These differences were consistent with the derived immune responses.

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