FcγR-TLR Cross-Talk Enhances TNF Production by Human Monocyte-Derived DCs via IRF5-Dependent Gene Transcription and Glycolytic Reprogramming.

Antigen-presenting cells (APCs) such as dendritic cells (DCs) are crucial for initiation of adequate inflammatory responses, which critically depends on the cooperated engagement of different receptors. In addition to pattern recognition receptors (PRRs), Fc gamma receptors (FcγRs) have recently been identified to be important in induction of inflammation by DCs. FcγRs that recognize IgG immune complexes, which are formed upon opsonization of pathogens, induce pro-inflammatory cytokine production through cross-talk with PRRs such as Toll-like receptors (TLRs).

Fc gamma receptor IIa suppresses type I and III interferon production by human myeloid immune cells.

Type I and type III interferons (IFNs) are fundamental for antiviral immunity, but prolonged expression is also detrimental to the host. Therefore, upon viral infection high levels of type I and III IFNs are followed by a strong and rapid decline. However, the mechanisms responsible for this suppression are still largely unknown.

Fc gamma receptor-TLR cross-talk elicits pro-inflammatory cytokine production by human M2 macrophages.

M2 macrophages suppress inflammation in numerous disorders, including tumour formation, infection and obesity. However, the exact role of M2 macrophages in the context of several other diseases is still largely undefined. We here show that human M2 macrophages promote inflammation instead of suppressing inflammation on simultaneous exposure to complexed IgG (c-IgG) and TLR ligands, as occurs in the context of diseases such as rheumatoid arthritis (RA).

Vitamin D3 metabolite calcidiol primes human dendritic cells to promote the development of immunomodulatory IL-10-producing T cells.

Vitamin D is recognized as a potent immunosuppressive drug. The suppressive effects of vitamin D are attributed to its physiologically active metabolite 1,25 dihydroxy vitamin D3 (calcitriol), which was shown, to prime dendritic cells (DCs) to promote the development of regulatory T (Treg) cells. Despite the potential benefit in treating autoimmune diseases, clinical application of calcitriol is hindered by deleterious side effects manifested by hypercalcemia and hypercalciuria.

FcγRIIa cross-talk with TLRs, IL-1R, and IFNγR selectively modulates cytokine production in human myeloid cells.

Myeloid antigen-presenting cells (APCs) tailor immune responses to the pathogen involved through the production of specific pro- and anti-inflammatory cytokines. It is becoming increasingly clear that the ultimate cytokine profile produced by myeloid APCs crucially depends on interaction between multiple pathogen recognizing receptors. In this respect, we recently identified an important role for cross-talk between Fc gamma receptor IIa (FcγRIIa) and Toll-like receptors (TLRs) in human dendritic cells (DCs), which induces anti-bacterial immunity through the selective induction of TNFα and Th17-promoting cytokines.

Langerhans cells favor skin flora tolerance through limited presentation of bacterial antigens and induction of regulatory T cells.

The mechanisms preventing detrimental T-cell responses against commensal skin bacteria remain elusive. Using monocyte-derived and skin-derived dendritic cells (DCs), we demonstrate that epidermal Langerhans cells (LCs), the DCs in the most superficial layer of the skin, have a poor capacity to internalize bacteria because of low expression of FcγRIIa. Furthermore, LCs show deficiency in processing and major histocompatibility complex II (MHC-II)-restricted presentation of bacterial antigens, as a result of a decreased expression of molecules involved in these functionalities.

Intradermal application of vitamin D3 increases migration of CD14+ dermal dendritic cells and promotes the development of Foxp3+ regulatory T cells.

The active form of vitamin D3 (VitD) is a potent immunosuppressive drug. Its effects are mediated in part through dendritic cells (DCs) that promote the development of regulatory T cells (Tregs). However, it remains elusive how VitD would influence the different human skin DC subsets, e.

Viral dsRNA-activated human dendritic cells produce IL-27, which selectively promotes cytotoxicity in naive CD8+ T cells.

Viral recognition programs DCs to express Signal 3 molecules that promote the differentiation of effector CD8(+) T cells. Besides IL-12, another DC-derived IL-12 family member, IL-27, has been reported to contribute herein, but its specific role is not well understood. Here, we show that whereas IL-12 potently induces inflammatory cytokines (i.

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

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.

CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation.

IL-17-producing CD4(+) T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via the CD5 or CD6 lymphocyte receptors forms a superior pathway for human Th17-priming.

Cutting edge: virus selectively primes human langerhans cells for CD70 expression promoting CD8+ T cell responses.

The two outermost compartments of skin are populated by different Ag-presenting dendritic cell types. Epidermal Langerhans cells (LCs) are evolutionarily adapted to the continuous presence of harmless skin commensals by the selective lack of cell surface TLRs that sense bacteria. In this article, we analyze the ability of LCs and dermal dendritic cells (DDCs) to respond to virus infection.

Genetically Modified Lactococcus lactis for Delivery of Human Interleukin-10 to Dendritic Cells.

Interleukin-10 (IL-10) plays an indispensable role in mucosal tolerance by programming dendritic cells (DCs) to induce suppressor Th-cells. We have tested the modulating effect of L. lactis secreting human IL-10 (L.

Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells.

Background: The vitamin D metabolite 1,25(OH)2D3 (VitD3) is a potent immunosuppressive drug and, among others, is used for topical treatment of psoriasis. A proposed mechanism of VitD3-mediated suppression is priming of dendritic cells (DCs) to induce regulatory T (Treg) cells.

Objective: Currently, there is confusion about the phenotype of VitD3-induced Treg cells and the DC-derived molecules driving their development.

IL-17 and IL-22 in atopic allergic disease.

A long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role for IL-17-producing (Th17) and IL-22-producing (Th22) T helper cells in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogenesis of allergic diseases. Here we re-evaluate the role of T helper cells, with special focus on the Th17 and Th22 subsets in allergic asthma and atopic dermatitis.

Gammadelta T cell receptors without a job.

In this issue of Immunity, the studies by Sutton et al. (2009) and Martin et al. (2009) indicate that gammadelta T cells are innate cells that rapidly produce interleukin (IL)-17 in response to cytokines or pathogens without the need for T cell receptor engagement.

Aberrant function of peripheral blood myeloid and plasmacytoid dendritic cells in atopic dermatitis patients.

Background: Dendritic cells (DCs) can act both as innate cells in host defense and as antigen-presenting cells for naive T cells in adaptive immunity. These functions, among others, are determined by the level of production of particular cytokines. Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by an initial phase predominated by T(H)2 cytokines that switches into a second, more chronic T(H)1-dominated eczematous phase.

Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells.

How the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed human DCs to promote IL-17 production in memory Th cells through the nucleotide oligomerization domain 2 (NOD2)-ligand muramyldipeptide (MDP), a derivative of bacterial peptidoglycan. MDP enhanced obligate bacterial Toll-like receptor (TLR) agonist induction of IL-23 and IL-1, which promoted IL-17 expression in T cells.

Interleukin-17 in inflammatory skin disorders.

Purpose Of Review: Recently, a novel and unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from Th1 and Th2 cells, was discovered. The question is addressed as to what extent inflammatory skin diseases are associated with the actions of this newly discovered Th17 cell subset.

Recent Findings: Th17 cells are involved in protection against bacterial pathogens.

Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation.

Ligation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-kappaB signaling, as well as late expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-kappaB pathway using the NEMO-binding domain peptide or the noncanonical NF-kappaB pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-kappaB signaling. Also, noncanonical NF-kappaB signaling down-regulates proinflammatory cytokine production in DCs.

An improved protocol for generation of immuno-potent dendritic cells through direct electroporation of CD14+ monocytes.

In this study we demonstrate a novel protocol showing that electroporation of CD14+ monocytes directly isolated from blood with green fluorescent protein (GFP) RNA results in a 3-fold higher yield of antigen presenting dendritic cells (DCs) when compared to conventional methods employing immature DCs for electroporation. We further show a stable electroporation efficacy resulting in 60% of GFP positive cells. Expression of co-stimulatory molecules and maturation markers such as CD80, CD86, CD83 as well of the chemokine receptor 7 (CCR7) was found in 90% of the mature DCs.

Loss of TLR2, TLR4, and TLR5 on Langerhans cells abolishes bacterial recognition.

It is unknown whether closely related epidermal dendritic cells, Langerhans cells (LCs), and dermal dendritic cells (DDCs) have unique functions. In this study, we show that human DDCs have a broad TLR expression profile, whereas human LCs have a selective impaired expression of cell surface TLR2, TLR4, and TLR5, all involved in bacterial recognition. This distinct TLR expression profile is acquired during the TGF-beta1-driven development of LCs in vitro.

Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9.

Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). The functional responses of keratinocytes to different PAMPs have not yet been fully established.

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

CD11c(+) 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.

Differential expression of inflammatory chemokines by Th1- and Th2-cell promoting dendritic cells: a role for different mature dendritic cell populations in attracting appropriate effector cells to peripheral sites of inflammation.

Protective immunity to pathogens depends on efficient immune responses adapted to the type of pathogen and the infected tissue. Dendritic cells (DC) play a pivotal role in directing the effector T cell response to either a protective T helper type 1 (Th1) or type 2 (Th2) phenotype. Human monocyte-derived DC can be differentiated into Th1-, Th2- or Th1/Th2-promoting DC in vitro upon activation with microbial compounds or cytokines.