CNBP, REL, and BHLHE40 variants are associated with IL-12 and IL-10 responses and tuberculosis risk

AbstractRationaleThe major human genes regulating M. tuberculosis (Mtb)-induced immune responses and tuberculosis (TB) susceptibility are poorly understood. Although IL-12 and IL-10 are critical for TB pathogenesis, the genetic factors that regulate their expression are unknown. CNBP, REL, and BHLHE40 are master regulators of IL-12 and IL-10 signaling.ObjectivesTo determine whether common human genetic variation in CNBP, REL and BHLHE40 is associated with IL-12 and IL-10 expression, adaptive immune responses to mycobacteria, and susceptibility to TB.Methods and Main MeasurementsWe characterized the association between common variants in CNBP, REL, and BHLHE40 and innate immune responses in dendritic cells and monocyte-derived macrophages (MDM), BCG-specific T cell responses, and susceptibility to pediatric and adult TB.ResultsSNP BHLHE40 rs4496464 was associated with increased BHLHE40 expression in MDMs and increased IL-10 from both peripheral blood dendritic cells and MDMs after LPS and TB whole cell lysate stimulation. SNP BHLHE40 rs11130215, in linkage disequilibrium with rs4496464, was associated with increased BCG-specific IL2+CD4+ T cell responses and decreased risk for pediatric TB in South Africa. SNPs REL rs842634 and CNBP rs11709852 were associated with increased IL-12 production from dendritic cells, and SNP REL rs842618, in linkage disequilibrium with rs842634, was associated with increased risk for TB meningitis.ConclusionsGenetic variation in CNBP, REL, and BHLHE40 is associated with IL-12 and IL-10 cytokine response and TB clinical outcomes. Common human genetic regulation of well-defined intermediate cellular traits provides insights into mechanisms of TB pathogenesis.

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A simple self-adjuvanting biomimetic nanovaccine self-assembled with the conjugate of phospholipids and nucleotides can induce a strong cancer immunotherapeutic effect

Biomaterials Science ◽

10.1039/d0bm01333a ◽

2021 ◽

Vol 9 (1) ◽

pp. 84-92

Author(s):

Dan Liu ◽

Jiale Liu ◽

Bing Ma ◽

Bo Deng ◽

Xigang Leng ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Cpg Odn ◽

Cross Presentation ◽

Cell Responses ◽

Self Assembled ◽

Cancer Immunotherapeutic

The biomimetic nanovaccines not only promoted antigens endocytosis into dendritic cells via receptor-mediated pathways but also induced antigens cross-presentation eliciting CD8+ T-cell responses. CPG-ODN as an adjuvant further enhanced the anti-tumor immune responses.

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

Blood ◽

10.1182/blood-2002-10-3063 ◽

2003 ◽

Vol 101 (9) ◽

pp. 3520-3526 ◽

Cited By ~ 234

Author(s):

Jean-François Fonteneau ◽

Michel Gilliet ◽

Marie Larsson ◽

Ida Dasilva ◽

Christian Münz ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Influenza Virus ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Cell Responses ◽

Adaptive Immune

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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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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