Leukocyte Immunoglobulin-Like Receptors Maintain Unique Antigen-Presenting Properties of Circulating Myeloid Dendritic Cells in HIV-1-Infected Elite Controllers

ABSTRACT Elite controllers maintain undetectable levels of HIV-1 replication in the absence of antiretroviral therapy, but the correlates of immune protection in this patient population are ill defined. Here, we demonstrate that in comparison to patients with progressive HIV-1 infection or healthy persons not infected with HIV-1, elite controllers have circulating myeloid dendritic cells with significantly increased antigen-presenting properties, while their ability to secrete proinflammatory cytokines is substantially diminished. This unique functional profile is associated with a distinct surface expression pattern of immunomodulatory leukocyte-immunoglobulin-like receptors (LILR) and a strong and selective upregulation of LILRB1 and LILRB3. Blockade of these two receptors by monoclonal antibodies or short interfering RNA (siRNA) abrogated the specific antigen-presenting properties of dendritic cells, implying an important regulatory role of these molecules. These data reveal previously unrecognized innate components of immune protection against HIV-1 in elite controllers and offer novel perspectives for the manipulation of host immunity for the prevention and treatment of HIV-1 infection.

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Soluble HLA-G Inhibits Myeloid Dendritic Cell Function in HIV-1 Infection by Interacting with Leukocyte Immunoglobulin-Like Receptor B2

Journal of Virology ◽

10.1128/jvi.01292-10 ◽

2010 ◽

Vol 84 (20) ◽

pp. 10784-10791 ◽

Cited By ~ 31

Author(s):

Jinghe Huang ◽

Patrick Burke ◽

Yue Yang ◽

Katherine Seiss ◽

Jill Beamon ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Function ◽

Critical Role ◽

Antigen Presenting Cells ◽

Hla Class I ◽

Elite Controllers ◽

Myeloid Dendritic Cells ◽

Soluble Hla ◽

Antigen Presenting ◽

Hiv 1

ABSTRACT Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons.

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Functional Impairment of Myeloid Dendritic Cells during Advanced Stage of HIV-1 Infection: Role of Factors Regulating Cytokine Signaling

PLoS ONE ◽

10.1371/journal.pone.0140852 ◽

2015 ◽

Vol 10 (10) ◽

pp. e0140852 ◽

Cited By ~ 6

Author(s):

Meenakshi Sachdeva ◽

Aman Sharma ◽

Sunil K. Arora

Keyword(s):

Dendritic Cells ◽

Functional Impairment ◽

Cytokine Signaling ◽

Advanced Stage ◽

Myeloid Dendritic Cells ◽

Hiv 1

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Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition

Blood ◽

10.1182/blood-2006-03-010918 ◽

2006 ◽

Vol 108 (6) ◽

pp. 1957-1964 ◽

Cited By ~ 47

Author(s):

Fedde Groot ◽

Toni M. M. van Capel ◽

Martien L. Kapsenberg ◽

Ben Berkhout ◽

Esther C. de Jong

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Sexual Transmission ◽

Innate Immune ◽

Innate Immune Responses ◽

Myeloid Dendritic Cells ◽

Different Types ◽

Plasmacytoid Dcs ◽

Antigen Presenting ◽

Hiv 1

AbstractCD11c+ myeloid dendritic cells (MDCs) and CD11c– CD123+ plasmacytoid DCs (PDCs) have been identified as main human DC subsets. MDCs are professional antigen-presenting cells for T cells, and include Langerhans cells, dermal DCs, and interstitial DCs. They have been associated with HIV-1 capture and sexual transmission, whereas PDCs play an important role in the innate immune responses to different types of viruses, including HIV-1. To compare the influence of MDCs and PDCs on HIV-1 infection of T cells, we isolated donor-matched MDCs and PDCs from peripheral blood, activated them by adding different maturation-inducing compounds, and cocultured them with T cells and HIV-1. We found that MDCs enhance HIV-1 infection through capture of the virus and subsequent transmission to T cells, and that differently matured MDC subsets have different HIV-1 transmission efficiencies. These differences were not due to soluble factors, viral capture differences, or the expression of integrins ICAM-1, -2, -3, or LFA-1. In contrast, regardless of their state of maturation, PDCs inhibit HIV-1 replication in T cells through the secretion of IFNα and an additional, unidentified small molecule. This study shows that the 2 main types of DCs have opposing roles in HIV-1 infection of T cells.

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A positive feedback loop reinforces the allergic immune response in human peanut allergy

Journal of Experimental Medicine ◽

10.1084/jem.20201793 ◽

2021 ◽

Vol 218 (7) ◽

Author(s):

Xiaoying Zhou ◽

Wong Yu ◽

Shu-Chen Lyu ◽

Claudia Macaubas ◽

Bryan Bunning ◽

...

Keyword(s):

Dendritic Cells ◽

Positive Feedback ◽

Feedback Loop ◽

Specific Antigen ◽

Oral Immunotherapy ◽

Food Allergies ◽

Cellular Mechanisms ◽

Myeloid Dendritic Cells ◽

Positive Feedback Loop ◽

Antigen Presenting

Food allergies are a leading cause of anaphylaxis, and cellular mechanisms involving antigen presentation likely play key roles in their pathogenesis. However, little is known about the response of specific antigen-presenting cell (APC) subsets to food allergens in the setting of food allergies. Here, we show that in peanut-allergic humans, peanut allergen drives the differentiation of CD209+ monocyte-derived dendritic cells (DCs) and CD23+ (FcєRII) myeloid dendritic cells through the action of allergen-specific CD4+ T cells. CD209+ DCs act reciprocally on the same peanut-specific CD4+ T cell population to reinforce Th2 cytokine expression in a positive feedback loop, which may explain the persistence of established food allergy. In support of this novel model, we show clinically that the initiation of oral immunotherapy (OIT) in peanut-allergic patients is associated with a decrease in CD209+ DCs, suggesting that breaking the cycle of positive feedback is associated with therapeutic effect.

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Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers

Journal of Clinical Investigation ◽

10.1172/jci146136 ◽

2021 ◽

Vol 131 (9) ◽

Author(s):

Ciputra Adijaya Hartana ◽

Yelizaveta Rassadkina ◽

Ce Gao ◽

Enrique Martin-Gayo ◽

Bruce D. Walker ◽

...

Keyword(s):

Dendritic Cells ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Metabolic Function ◽

Elite Controllers ◽

Myeloid Dendritic Cells ◽

Hiv 1

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A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers

Genome Biology ◽

10.1186/s13059-017-1385-x ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 15

Author(s):

Enrique Martin-Gayo ◽

Michael B. Cole ◽

Kellie E. Kolb ◽

Zhengyu Ouyang ◽

Jacqueline Cronin ◽

...

Keyword(s):

Dendritic Cells ◽

Elite Controllers ◽

Computational Framework ◽

Antiviral State ◽

Hiv 1

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Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-γ production and the induction of Th1 cell differentiation

Blood ◽

10.1182/blood-2006-11-059246 ◽

2007 ◽

Vol 110 (2) ◽

pp. 553-560 ◽

Cited By ~ 44

Author(s):

Naoki Tokumasa ◽

Akira Suto ◽

Shin-ichiro Kagami ◽

Shunsuke Furuta ◽

Koichi Hirose ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Differentiation ◽

Cpg Odn ◽

T Helper ◽

Dc Functions ◽

Th1 Cell ◽

Th2 Cell ◽

Ifn Γ ◽

Antigen Presenting

Abstract It is well documented that dendritic cells (DCs), representative antigen-presenting cells, are important sources of Th1-promoting cytokines and are actively involved in the regulation of T-helper–cell differentiation. However, the intracellular event that regulates this process is still largely unknown. In this study, we examined the role of Tyk2, a JAK kinase that is involved in the signaling pathway under IL-12 and IL-23, in DC functions. While the differentiation and maturation of DCs was normal in Tyk2-deficient (Tyk2−/−) mice, IL-12–induced Stat4 phosphorylation was diminished in Tyk2−/− DCs. IL-12–induced IFN-γ production was also significantly diminished in Tyk2−/− DCs to levels similar to those in Stat4−/− DCs. Interestingly, Tyk2−/− DCs were defective in IL-12 and IL-23 production upon stimulation with CpG ODN. Furthermore, Tyk2−/− DCs were impaired in their ability to induce Th1-cell differentiation but not Th2-cell differentiation. Taken together, these results indicate that the expression of Tyk2 in DCs is crucial for the production of Th1-promoting cytokines such as IL-12 and IFN-γ from DCs and thereby for the induction of antigen-specific Th1-cell differentiation.

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Levels of plasmacytoid dendritic cells and type-2 myeloid dendritic cells are reduced in peripheral blood of patients with primary Sjögren's syndrome

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.118158 ◽

2009 ◽

Vol 69 (6) ◽

pp. 1235-1238 ◽

Cited By ~ 31

Author(s):

Petra Vogelsang ◽

Johan G Brun ◽

Gunnvor Øijordsbakken ◽

Kathrine Skarstein ◽

Roland Jonsson ◽

...

Keyword(s):

Dendritic Cells ◽

Sjögren’S Syndrome ◽

Peripheral Blood ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Healthy Controls ◽

Myeloid Dendritic Cells ◽

Antigen Presenting ◽

Sjögren‘S Syndrome

ObjectiveSjögren's syndrome (SS) is a lymphoproliferative autoimmune disease, characterised by dryness of the mouth and eyes. Dendritic cells (DC) are potent antigen-presenting cells crucial for initiating and maintaining primary immune responses. This study quantified interferon-producing plasmacytoid DC (pDC) and two myeloid DC subsets (mDC1 and mDC2) in peripheral blood (PB) from primary SS (pSS) patients and healthy controls.MethodsBlood samples from 31 pSS patients and 28 gender and age-matched healthy controls were analysed by flow cytometry using the Miltenyi Blood DC enumeration kit. The presence of pDC in salivary glands (SG) from pSS patients was analysed by immunohistochemistry.ResultsPatients with pSS had significantly less pDC and mDC2 in PB compared with healthy controls. Moreover, pDC are present in SG from patients with pSS.ConclusionPatients with pSS have alterations among DC populations in PB, and pDC are present in the SG, suggesting a potential role of these cells in SS.

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