The inhibitory receptor LILRB1 modulates the differentiation and regulatory potential of human dendritic cells

Abstract Dendritic cells (DCs) link innate and adaptive immunity, initiating and regulating effector cell responses. They ubiquitously express members of the LILR (ILT, LIR, CD85) family of molecules, some of which recognize self-HLA molecules, but little is known of their possible functions in DC biology. We demonstrate that the inhibitory receptor LILRB1 (ILT2, LIR1, CD85j) is selectively up-regulated during DC differentiation from monocyte precursors in culture. Continuous ligation of LILRB1 modulated cellular differentiation, conferred a unique phenotype upon the resultant cells, induced a profound resistance to CD95-mediated cell death, and inhibited secretion of cytokines IL-10, IL-12p70, and TGF-β. These features remained stable even after exposure of the cells to bacterial LPS. Ligated DCs exhibited poor stimulatory activity for primary and memory T-cell proliferative responses, but this was substantially reversed by blockade of CD80 or its preferred ligand CTLA-4, or by depleting CD4+ CD25+ CD127lo regulatory T cells. Our findings suggest that ligation of LILRB1 on DCs by self-HLA molecules may play a key role in controlling the balance between the induction and suppression of adaptive immune responses.

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IgG opsonization of bacteria promotes Th17 responses via synergy between TLRs and FcγRIIa in human dendritic cells

Blood ◽

10.1182/blood-2011-12-399931 ◽

2012 ◽

Vol 120 (1) ◽

pp. 112-121 ◽

Cited By ~ 60

Author(s):

Jeroen den Dunnen ◽

Lisa T. C. Vogelpoel ◽

Tomasz Wypych ◽

Femke J. M. Muller ◽

Leonie de Boer ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Th17 Cell ◽

Th17 Cells ◽

Cell Responses ◽

Adaptive Immune ◽

Enhanced Production ◽

Multiple Receptors ◽

Human Dendritic Cells ◽

Different Levels

Abstract Dendritic cells (DCs) are essential in inducing adaptive immune responses against bacteria by expressing cytokines that skew T-cell responses toward protective Th17 cells. Although it is widely recognized that induction of these cytokines by DCs involves activation of multiple receptors, it is still incompletely characterized which combination of receptors specifically skews Th17-cell responses. Here we have identified a novel role for FcγRIIa in promoting human Th17 cells. Activation of DCs by bacteria opsonized by serum IgG strongly promoted Th17 responses, which was FcγRIIa-dependent and coincided with enhanced production of selected cytokines by DCs, including Th17-promoting IL-1β and IL-23. Notably, FcγRIIa stimulation on DCs did not induce cytokine production when stimulated individually, but selectively amplified cytokine responses through synergy with TLR2, 4, or 5. Importantly, this synergy is mediated at 2 different levels. First, TLR-FcγRIIa costimulation strongly increased transcription of pro-IL-1β and IL-23p19. Second, FcγRIIa triggering induced activation of caspase-1, which cleaves pro-IL-1β into its bioactive form and thereby enhanced IL-1β secretion. Taken together, these data identified cross-talk between TLRs and FcγRIIa as a novel mechanism by which DCs promote protective effector Th17-cell responses against bacteria.

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β-Defensins: Linking Innate and Adaptive Immunity Through Dendritic and T Cell CCR6

Science ◽

10.1126/science.286.5439.525 ◽

1999 ◽

Vol 286 (5439) ◽

pp. 525-528 ◽

Cited By ~ 1221

Author(s):

D. Yang ◽

O. Chertov ◽

S. N. Bykovskaia ◽

Q. Chen ◽

M. J. Buffo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Cytoplasmic Membrane ◽

Memory T Cells ◽

Innate And Adaptive Immunity ◽

Adaptive Immune ◽

Microbial Invasion ◽

Immature Dendritic Cells ◽

Chemokine Ligand

Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human β-defensins are also chemotactic for immature dendritic cells and memory T cells. Human β-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The β-defensin–induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by β-defensin. Thus, β-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.

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Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity

Journal of Immunology Research ◽

10.1155/2016/5134329 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Sandra Winning ◽

Joachim Fandrey

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Adaptive Immune Response ◽

Mature Dendritic Cell ◽

Innate And Adaptive Immunity ◽

Cell Functions ◽

Adaptive Immune ◽

Oxygen Shortage

Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to linkin vitroresults to actualin vivostudies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity.

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Mannose Receptor Targeting of Tumor Antigen pmel17 to Human Dendritic Cells Directs Anti-Melanoma T Cell Responses via Multiple HLA Molecules

The Journal of Immunology ◽

10.4049/jimmunol.172.5.2845 ◽

2004 ◽

Vol 172 (5) ◽

pp. 2845-2852 ◽

Cited By ~ 80

Author(s):

Venky Ramakrishna ◽

John F. Treml ◽

Laura Vitale ◽

John E. Connolly ◽

Thomas O’Neill ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Tumor Antigen ◽

T Cell Responses ◽

Mannose Receptor ◽

Receptor Targeting ◽

Cell Responses ◽

Human Dendritic Cells ◽

Hla Molecules

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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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Messing with the Sentinels—The Interaction of Staphylococcus aureus with Dendritic Cells

Microorganisms ◽

10.3390/microorganisms6030087 ◽

2018 ◽

Vol 6 (3) ◽

pp. 87 ◽

Cited By ~ 5

Author(s):

Murthy Darisipudi ◽

Maria Nordengrün ◽

Barbara Bröker ◽

Vincent Péton

Keyword(s):

Staphylococcus Aureus ◽

Immune Response ◽

Dendritic Cells ◽

Immune Responses ◽

Respiratory Diseases ◽

Adaptive Immune Responses ◽

Immune Effector ◽

Cell Responses ◽

Adaptive Immune ◽

Aureus Infection

Staphylococcus aureus (S. aureus) is a dangerous pathogen as well as a frequent colonizer, threatening human health worldwide. Protection against S. aureus infection is challenging, as the bacteria have sophisticated strategies to escape the host immune response. To maintain equilibrium with S. aureus, both innate and adaptive immune effector mechanisms are required. Dendritic cells (DCs) are critical players at the interface between the two arms of the immune system, indispensable for inducing specific T cell responses. In this review, we highlight the importance of DCs in mounting innate as well as adaptive immune responses against S. aureus with emphasis on their role in S. aureus-induced respiratory diseases. We also review what is known about mechanisms that S. aureus has adopted to evade DCs or manipulate these cells to its advantage.

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Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽

10.1038/s41541-021-00314-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Mauro Di Pilato ◽

Miguel Palomino-Segura ◽

Ernesto Mejías-Pérez ◽

Carmen E. Gómez ◽

Andrea Rubio-Ponce ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Vaccinia Virus ◽

Adaptive Immune System ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

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Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

International Journal of Molecular Sciences ◽

10.3390/ijms22105386 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5386

Author(s):

Maria Namwanje ◽

Bijay Bisunke ◽

Thomas V. Rousselle ◽

Gene G. Lamanilao ◽

Venkatadri S. Sunder ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Therapeutic Potential ◽

Ex Vivo ◽

Mitochondrial Dynamics ◽

Graft Loss ◽

Kidney Injury ◽

Adaptive Immune ◽

Consumption Rates ◽

Regulatory Phenotype

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.

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Effects of Staphylococcus aureus Bacteriophage K on Expression of Cytokines and Activation Markers by Human Dendritic Cells In Vitro

Viruses ◽

10.3390/v10110617 ◽

2018 ◽

Vol 10 (11) ◽

pp. 617 ◽

Cited By ~ 5

Author(s):

Helen Freyberger ◽

Yunxiu He ◽

Amanda Roth ◽

Mikeljon Nikolich ◽

Andrey Filippov

Keyword(s):

Staphylococcus Aureus ◽

Dendritic Cells ◽

Inflammatory Response ◽

Adaptive Immune Response ◽

Human Monocyte ◽

Activation Markers ◽

Mhc I ◽

Adaptive Immune ◽

Human Dendritic Cells

A potential concern with bacteriophage (phage) therapeutics is a host-versus-phage response in which the immune system may neutralize or destroy phage particles and thus impair therapeutic efficacy, or a strong inflammatory response to repeated phage exposure might endanger the patient. Current literature is discrepant with regard to the nature and magnitude of innate and adaptive immune response to phages. The purpose of this work was to study the potential effects of Staphylococcus aureus phage K on the activation of human monocyte-derived dendritic cells. Since phage K acquired from ATCC was isolated around 90 years ago, we first tested its activity against a panel of 36 diverse S. aureus clinical isolates from military patients and found that it was lytic against 30/36 (83%) of strains. Human monocyte-derived dendritic cells were used to test for an in vitro phage-specific inflammatory response. Repeated experiments demonstrated that phage K had little impact on the expression of pro- and anti-inflammatory cytokines, or on MHC-I/II and CD80/CD86 protein expression. Given that dendritic cells are potent antigen-presenting cells and messengers between the innate and the adaptive immune systems, our results suggest that phage K does not independently affect cellular immunity or has a very limited impact on it.

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