scholarly journals Dendritic Cells and NK Cells Stimulate Bystander T Cell Activation in Response to TLR Agonists through Secretion of IFN-αβ and IFN-γ

2005 ◽  
Vol 174 (2) ◽  
pp. 767-776 ◽  
Author(s):  
Arun T. Kamath ◽  
Christopher E. Sheasby ◽  
David F. Tough
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tlr Agonists ◽  
Ifn Γ

Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3253-3262 ◽  
Author(s):  
Thanyalak Tha-In ◽  
Herold J. Metselaar ◽  
Hugo W. Tilanus ◽  
Zwier M. A. Groothuismink ◽  
Ernst J. Kuipers ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Intravenous Immunoglobulins ◽  
Interferon Γ ◽  
T Cell Priming ◽  
Induced Apoptosis

AbstractThe modes of action of intravenous immunoglobulins (IVIgs) in exerting their immunomodulatory properties are broad and not fully understood. IVIgs can modulate the function of various immune cells, including suppressing the capacity of dendritic cells (DCs) to stimulate T cells. In the present study, we showed that DCs matured in the presence of IVIgs (IVIg-DCs) activated NK cells, and increased their interferon-γ production and degranulation. The activated NK cells induced apoptosis of the majority of IVIg-DCs. In consequence, only in the presence of NK cells, IVIg-DCs were 4-fold impaired in their T-cell priming capacity. This was due to NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) to IVIg-DCs, probably induced by IgG multimers, which could be abrogated by blockade of CD16 on NK cells. Furthermore, IVIg-DCs down-regulated the expression of NKp30 and KIR receptors, and induced the generation of CD56brightCD16−CCR7+ lymph node–type NK cells. Our results identify a novel pathway, in which IVIgs induce ADCC of mature DCs by NK cells, which downsizes the antigen-presenting pool and inhibits T-cell priming. By influencing the interaction between DCs and NK cells, IVIgs modulate the ability of the innate immunity to trigger T-cell activation, a mechanism that can “cool down” the immune system at times of activation.

scholarly journals Conferral of Enhanced Natural Killer Cell Function by KIR3DS1 in Early Human Immunodeficiency Virus Type 1 Infection

2008 ◽  
Vol 82 (10) ◽  
pp. 4785-4792 ◽  
Author(s):  
Brian R. Long ◽  
Lishomwa C. Ndhlovu ◽  
Jorge R. Oksenberg ◽  
Lewis L. Lanier ◽  
Frederick M. Hecht ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cd107a Expression ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT A flurry of recent reports on the role of activating and inhibitory forms of the killer cell immunoglobulin-like receptors (KIR) in natural killer (NK) cell activity against human immunodeficiency virus type 1 (HIV-1) have yielded widely divergent results. The role of the activating NK receptor encoded by the KIR3DS1 allele and its putative ligands, members of the HLA class I Bw4Ile80 cluster, in early HIV-1 disease is controversial. We selected 60 treatment-naïve adults for study from the OPTIONS cohort of individuals with early HIV-1 infection in San Francisco. We performed NK cell functional assays measuring gamma interferon (IFN-γ) and CD107a expression by NK cells in the unstimulated state and after stimulation by the major histocompatibility complex class I-deficient 721.221 B-lymphoblastoid cell line. In addition, we measured CD38 expression (a T-cell activation marker) on T and NK cells. Persons who have at least one copy of the KIR3DS1 gene had higher IFN-γ and CD107a expression in the unstimulated state compared to those who do not possess this gene. After stimulation, both groups experienced a large induction of IFN-γ and CD107a, with KIR3DS1 carriers achieving a greater amount of IFN-γ expression. Differences in effector activity correlating with KIR3DS1 were not attributable to joint carriage of HLA Bw4Ile80 and KIR3DS1. We detected a partial but not complete dependence of KIR3DS1 on the members of B*58 supertype (B*57 and B*58) leading to higher NK cell function. Possessing KIR3DS1 was associated with lower expression of CD38 on both CD8+ T and NK cells and with a loss or weakening of the known strong associations between CD8+ T-cell expression of CD38 mean fluorescence intensity and the HIV-1 viral load. We observed that possessing KIR3DS1 was associated with higher NK cell effector functions in early HIV-1 disease, despite the absence of HLA Bw4Ile80, a putative ligand of KIR3DS1. Carriage of KIR3DS1 was associated with diminished CD8+ T-cell activation, as determined by expression of CD38, and a disruption of the traditional relationship between viral load and activation in HIV-1 disease, which may lead to better clinical outcomes for these individuals.

scholarly journals Activation-Induced FoxP3 Expression Regulates Cytokine Production in Conventional T Cells Stimulated with Autologous Dendritic Cells

2012 ◽  
Vol 19 (10) ◽  
pp. 1583-1592 ◽  
Author(s):  
Derek J. Cavatorta ◽  
Hollis N. Erb ◽  
M. Julia Felippe
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Foxp3 Expression ◽  
Interleukin 4 ◽  
Immunosuppressive Cytokine ◽  
Ifn Γ ◽  
Effector Cytokines

ABSTRACTA defining feature of dendritic cells (DCs) is their ability to induce the proliferation of autologous T cells in the absence of foreign antigen—a process termed the “autologous mixed leukocyte reaction” (AMLR). We report that equine monocyte-derived DCs, but not macrophages, are potent inducers of the AMLR. The response is contact dependent and major histocompatibility complex class II dependent and primarily involves CD3+CD4+CD8−T cells. Upon stimulation with DCs or the mitogen concanavalin A, a subset of the proliferating T cells expresses the regulatory T-cell (Treg) transcription factor FoxP3. Although many of these FoxP3+T cells are capable of producing the effector cytokines interleukin-4 (IL-4) and gamma interferon (IFN-γ), they are more likely to produce IL-10 and less likely to produce IFN-γ than equivalent FoxP3−cells. Therefore, FoxP3 expression is an inherent component of equine T cell activation and is associated with a more immunosuppressive cytokine profile. These results confirm that FoxP3 expression in the horse, in contrast to the mouse, is regulated similarly to FOXP3 expression in humans and provide evidence that FoxP3 expression by conventional T cells may help regulate the developing immune response.

scholarly journals P04.04 Multifunctional antibody construct for in vivo targeting of dendritic cells as a therapeutic vaccination strategy in AML

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A38.1-A38
Author(s):  
S Schmitt ◽  
A Lohner ◽  
K Deiser ◽  
A Maiser ◽  
M Rothe ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Response ◽  
Tlr Agonists ◽  
Cross Presentation ◽  
Tnf Α

BackgroundDendritic cells (DCs) are antigen-presenting cells that induce antigen-specific T-cell responses. Therefore, they are used as tools and targets for anti-tumor vaccination. In contrast to T-cell based immunotherapies, that are often limited to surface antigens, DC-based vaccination strategies open up new therapeutic options by utilizing highly abundant intracellular tumor antigens as a target source. Among those, recent interest has been focused on the identification of neoantigens derived from tumor-specific mutations. Especially mutated Nucleophosmin 1 (ΔNPM1) is a considered candidate for targeted therapy in acute myeloid leukemia (AML). We developed a multifunctional antibody construct consisting of a peptide domain including a variable T-cell epitope that is fused to an αCD40 single chain variable fragment (scFv) with agonistic function to target and activate dendritic cells in vivo. To potentiate therapeutic efficacy, toll-like receptor (TLR) agonists can be attached as co-stimulatory domains, thereby aiming to enhance cross-presentation of conjugated (neo)antigens to CD8+ T cells.Materials and MethodsFlow cytometry and microscopy-based binding and internalization experiments were performed using monocyte-derived dendritic cells (moDCs). Upregulation of surface markers (CD80, CD83, CD86, HLA-DR) as well as cytokine secretion (IL-6 and IL-12) indicated DC maturation. To validate peptide processing and presentation, moDCs were co-cultured with autologous as well as allogeneic T cells. IFN-γ and TNF-α secretion served as a readout for T-cell activation, peptide-MHC multimer staining for T-cell proliferation.ResultsFor proof-of-principle experiments, the multispecific antibody derivative was developed by fusing the αCD40 scFv to a cytomegalovirus (CMV)-specific peptide. The αCD40.CMV construct bound CD40 agonistically and showed efficient internalization into early endosomal compartments on immature moDCs. In co-cultures of immature and mature moDCs with autologous or allogeneic T cells, αCD40.CMV induced a significantly increased T-cell activation and proliferation compared to the control. The co-administration of αCD40.CMV with various TLR agonists as vaccine adjuvants resulted in a significant upregulation of DC maturation markers in comparison to αCD40.CMV only. Interestingly, not all adjuvants were able to enhance the T-cell response. To translate this principle to the AML setting, the CMV peptide sequence was replaced with the ΔNPM1-derived and HLA-A*02:01-binding neoantigen CLAVEEVSL. Cross-presentation to CD8+ T cells transduced with a ΔNPM1-specific T-cell receptor was proven by IFN-γ and TNF-α secretion in co-cultures with moDCs that have been pre-incubated with αCD40.ΔNPM1. The optimal vaccine adjuvant has yet to be identified.ConclusionsWe successfully demonstrated the development of a multifunctional antibody construct that specifically targets and stimulates DCs by an agonistic αCD40 scFv. It simultaneously delivers a T cell-specific peptide with a vaccine adjuvant to induce an efficient T-cell response. As neoantigens are promising targets and under intense investigaton, the αCD40.ΔNPM1 fusion protein is of high therapeutic interest. Thus, our approach displays a promising DC vaccination option for the treatment of AML.Disclosure InformationS. Schmitt: None. A. Lohner: None. K. Deiser: None. A. Maiser: None. M. Rothe: None. C. Augsberger: None. A. Moosmann: None. H. Leonhardt: None. N. Fenn: None. M. Griffioen: None. K. Hopfner: None. M. Subklewe: None.

scholarly journals NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells

2019 ◽  
Vol 11 ◽  
pp. 175883591989162 ◽  
Author(s):  
Naomi C. Bosch ◽  
Reinhard E. Voll ◽  
Caroline J. Voskens ◽  
Stefanie Gross ◽  
Barbara Seliger ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Cytotoxic T Lymphocyte ◽  
Innate Immune ◽  
Antitumor Effects ◽  
Cytokine Cocktail

Background: In therapeutic cancer vaccination, monocyte-derived dendritic cells (moDCs) efficiently activate specific T-cell responses; however, optimizing the activation of innate immune cells could support and improve the antitumor effects. A major disadvantage of moDCs matured with the standard cytokine cocktail (consisting of IL-1β, IL-6, TNFα, and PGE2) is their inability to secrete IL-12p70. IL-12 prominently activates natural killer (NK) cells, which are crucial in innate antitumor immunity, as they act as helper cells for the induction of a cytotoxic T lymphocyte (CTL) response and are also able to directly kill the tumor. Methods: Previously we have shown that triggering the NF-κB pathway in moDCs by transfection of mRNA encoding constitutively active IKKβ (caIKKβ) led to IL-12p70 secretion and improved the dendritic cells’ capability to activate and expand CTLs with a memory-like phenotype. In this study, we examined whether such dendritic cells could activate autologous NK cells. Results: moDCs matured with the standard cytokine cocktail followed by transfection with the caIKKβ-RNA were able to activate autologous NK cells, detected by the upregulation of CD54, CD69, and CD25 on the NK cells, their ability to secrete IFNγ, and their high lytic activity. Moreover, the ability of NK-cell activation was not diminished by simultaneous T-cell activation. Conclusion: The capacity of caIKKβ-DCs to activate both the adaptive and innate immune response indicates an enhanced potential for clinical efficacy.

scholarly journals CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

2021 ◽  
Author(s):  
Yan Yan ◽  
Wei Zhao ◽  
Wei Liu ◽  
Yan Li ◽  
Xu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
Cell Activation ◽  
Hbv Infection ◽  
Host Immune System ◽  
Tnf Α ◽  
Ifn Γ ◽  
High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

scholarly journals CD14 Expressing Precursors Give Rise to Highly Functional Conventional Dendritic Cells for Use as Dendritic Cell Vaccine

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3818
Author(s):  
Maud Plantinga ◽  
Denise A. M. H. van den Beemt ◽  
Ester Dünnebach ◽  
Stefan Nierkens
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cord Blood ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Activated T Cells

Induction of long-lasting immunity by dendritic cells (DCs) makes them attractive candidates for anti-tumor vaccination. Although DC vaccinations are generally considered safe, clinical responses remain inconsistent in clinical trials. This initiated studies to identify subsets of DCs with superior capabilities to induce effective and memory anti-tumor responses. The use of primary DCs has been suggested to overcome the functional limitations of ex vivo monocyte-derived DCs (moDC). The ontogeny of primary DCs has recently been revised by the introduction of DC3, which phenotypically resembles conventional (c)DC2 as well as moDC. Previously, we developed a protocol to generate cDC2s from cord blood (CB)-derived stem cells via a CD115-expressing precursor. Here, we performed index sorting and single-cell RNA-sequencing to define the heterogeneity of in vitro developed DC precursors and identified CD14+CD115+ expressing cells that develop into CD1c++DCs and the remainder cells brought about CD123+DCs, as well as assessed their potency. The maturation status and T-cell activation potential were assessed using flow cytometry. CD123+DCs were specifically prone to take up antigens but only modestly activated T-cells. In contrast, CD1c++ are highly mature and specialized in both naïve as well as antigen-experienced T-cell activation. These findings show in vitro functional diversity between cord blood stem cell-derived CD123+DC and CD1c++DCs and may advance the efficiency of DC-based vaccines.

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