Natural type I interferon-producing cells as a link between innate and adaptive immunity

Type I interferons (IFNs) are promptly produced upon invasion of pathogens, and activate a broad range of effector cells in the innate and adaptive immune system. Lin⁻CD4⁺CD11c⁻ plasmacytoid dendritic cell precursors (plasmacytoid pre-DCs) produce enormous amounts of type I IFNs in response to viruses and CpG DNA, thus corresponding to the previously described but not fully defined natural type I IFN-producing cells (IPCs). Plasmacytoid pre-DCs strongly express toll-like receptor (TLR) 7 and TLR9, in contrast to monocytes, which mainly express TLR1, 2, 4, 5, and 8, suggesting that these two DC precursors recognize different microbial molecules and that they may have developed through different evolutionary trails. Three different stimuli, CpG DNA plus CD40 ligand, interleukin-3 (IL-3), and herpes simplex virus, stimulate plasmacytoid pre-DCs to differentiate into DCs that induce distinct types of T helper cells, i.e., Th1, Th2, and IFN-γ- and IL-10-producing T cells, respectively. The remarkable versatility of plasmacytoid pre-DCs distinguishes them from other cell types in the immune system that have only limited functions, and suggests that these cells may play a key role in integrating the innate and adaptive aspects of various immune responses.     

Analysis of differential immune responses induced by innate and adaptive immunity following transplantation

The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation.     

Nod1-mediated innate immune recognition of peptidoglycan contributes to the onset of adaptive immunity

Recent evidence has suggested that signals other than those from Toll-like receptors (TLRs) could contribute to the elicitation of antigen-specific immunity. Therefore, we examined the role of the Nod-like receptor (NLR) family member, Nod1, in the generation of adaptive immune responses. Our findings show that innate immune sensing of peptidoglycan by Nod1 is key for priming antigen-specific T cell immunity and subsequent antibody responses in vivo. Nod1 stimulation alone was sufficient to drive antigen-specific immunity with a predominant Th2 polarization profile. In conjunction with TLR stimulation, however, Nod1 triggering was required to instruct the onset of Th1 and Th2 as well as Th17 immune pathways. Cells outside of the hematopoietic lineage provided the early signals necessary to orchestrate the development of Nod1-dependent immune responses. These findings highlight Nod1 as a key innate immune trigger in the local tissue microenvironment that drives the development of adaptive immunity.     

Immune response in human visceral leishmaniasis: analysis of the correlation between innate immunity cytokine profile and disease outcome

We investigated the cytokine profile of cells of the innate immune response and its association with active (ACT), asymptomatic (AS) and cured (CUR) human visceral leishmaniasis (VL), as well as noninfected (NI) subjects. The frequency of cytokine-producing cells was determined after short-term in vitro incubation of whole peripheral blood samples with soluble Leishmania antigen (SLA). Our data demonstrated a predominant type 2 cytokine profile in NI and ACT. In NI, we observed an increase of IL-4+ neutrophils, IL-10+ eosinophils besides a decrease of tumour necrosis factor (TNF)-alpha+ eosinophils/monocytes. Yet in ACT, we observed an increase of IL-4+ neutrophils and natural killer (NK) cells and IL-10+ monocytes, a reduced frequency of IL-12+ and IFN-gamma+ eosinophils and lower levels of TNF-alpha+ and IL-12+ monocytes. AS presented a mixed profile, characterized by an increase of IFN-gamma+ neutrophils/eosinophils and NK cells, of IL-12+ eosinophils/monocytes, as well as increase of IL-4+ neutrophils and NK cells and IL-10+ eosinophils/monocytes. In contrast, CUR was characterized by a type 1 response with an increase of IFN-gamma+ neutrophils/eosinophils and NK cells, associated with an increase in IL-12+ monocytes. In conclusion, we show a correlation between innate immune cytokine patterns and clinical status of VL, suggesting that these cells, in addition to other factors, may contribute to the cytokine microenvironment in which Leishmania-specific T cells are primed and to disease outcome.     

Effective control of viral infections by the adaptive immune system requires assistance from innate immunity

Evaluation of: Nakayama Y, Plisch EH, Sullivan JM et al. Role of PKR and type I IFNs in viral control during primary and secondary infection. PLoS Pathog. 6(6), e1000966 (2010). During acute viral infections, innate antiviral immunity has been extensively studied for its ability to inhibit and/or control viral replication while priming the adaptive immune system. Recently, these processes have been studied for their role in assisting adaptive immunity to effectively clear or control viral rechallenge. The paper under evaluation introduces the concept that functional innate immune mechanisms such as dsRNA-activated protein kinase (PKR) and type I interferons are critical in controlling viral replication during secondary lymphocyte choriomeningitis virus infection. Elegant adoptive transfer studies revealed that during lymphocyte choriomeningitis virus secondary infections, dependence of viral control relied on expression of these innate factors in virally infected cells and not in adaptive immune T cells. Such findings illustrate that functional adaptive responses are less effective in providing protection against reinfections in the absence of innate mechanisms. This demonstrates the importance of intact innate mechanisms when considering effective vaccine strategies.     

Chronic aspiration shifts the immune response from adaptive immunity to innate immunity in a murine model of asthma

Objective and design

The hypothesis that aspiration of gastric fluid drives the anti-ovalbumin response toward a Th2 reaction even in animals not prone to Th2 responses was evaluated.

Subjects

Forty-eight male C57BL/6 mice were used.

Methods

Mice were sensitized and challenged with ovalbumin starting 5?weeks prior to the initiation of weekly aspirations of either gastric fluid or normal saline as a control. Weekly aspiration continued during the course of exposure to ovalbumin.

Treatment

Aspiration consisted of 50?μl of gastric fluid with 50?μl of 0.9?% normal saline used as a control. Antigen exposure consisted of sensitization to ovalbumin via intraperitoneal injection on days 0 and 14 and challenge on day 21 with aerosolized antigen for 30?min.

Results

No evidence of a shift toward a Th2 response as a result of gastric fluid aspiration was seen in the Th1-prone strain utilized, although a profound down-regulation of a broad array of T cell-associated cytokines and chemokines and up-regulation of macrophage-associated markers was observed as a result of aspiration.

Conclusions

These data provide support for the hypothesis that the clinical association between asthma and gastroesophageal reflux disease (GERD) does not involve an exacerbation of asthma by GERD-associated aspiration of gastric fluid, but may cause immune reactions unrelated to the asthma pathology.     

Regulation of innate and adaptive immunity by the commensal microbiota

The microbial communities that inhabit the intestinal tract are essential for mammalian health. Communication between the microbiota and the host establishes and maintains immune homeostasis, enabling protective immune responses against pathogens while preventing adverse inflammatory responses to harmless commensal microbes. Specific bacteria, such as segmented filamentous bacteria, Clostridium species, and Bacteroides fragilis, are key contributors to immune homeostasis in the gut. The cellular and molecular interactions between intestinal microbes and the immune system are rapidly being elucidated. Here, we review advances in our understanding of the microbial populations that shape the mucosal immune system and create a protective defense that prevents infection while tolerating friendly commensals.     

Benznidazole, a drug employed in the treatment of Chagas' disease, down-regulates the synthesis of nitrite and cytokines by murine stimulated macrophages.

Benznidazole (BZL) is a nitroheterocyclic drug employed in the chemotherapy of Chagas' disease, a protozoan disease caused by Trypanosoma cruzi. Because this parasite mostly replicates in macrophages, we investigated whether BZL was likely to modify the synthesis of macrophage mediators such as nitrite, tumour necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6 and IL-10. Control and stimulated murine macrophages (lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma)) were treated with BZL and measurements were carried out in culture supernatants collected 24 h later. Synthesis of nitrite, IL-6 and IL-10 was maximal upon combined stimulation with LPS + IFN-gamma, whereas lower amounts of the three mediators were detected when both stimuli were given alone. BZL treatment significantly reduced nitrite, IL-6 and IL-10 production, to undetectable levels in some cases, particularly IL-6 and IL-10. LPS was the most potent stimulus of IL-1beta and TNF-alpha production, followed by LPS + IFN-gamma and IFN-gamma in decreasing order. BZL partly inhibited TNF-alpha synthesis, but this effect was smaller than that observed for nitrite, IL-6 and IL-10. LPS-induced production of IL-1beta was also affected by BZL. Semiquantification of gene expression for inducible nitric oxide synthase (iNOS) showed that BZL completely inhibited iNOS gene induction by IFN-gamma, and resulted in respective inhibitions of 30% and 50% with LPS- and LPS + IFN-gamma-stimulated cells. BZL was not cytotoxic on macrophage cultures, as shown by the lactate dehydrogenase activity. Besides its trypanocidal activity, BZL may also alter the balance between pro- and anti-inflammatory mediators with important consequences for the course of T. cruzi infection.     

The innate immune responses of colonic epithelial cells to Trichuris muris are similar in mouse strains that develop a type 1 or type 2 adaptive immune response

Trichuris muris resides in intimate contact with its host, burrowing within cecal epithelial cells. However, whether the enterocyte itself responds innately to T. muris is unknown. This study investigated for the first time whether colonic intestinal epithelial cells (IEC) produce cytokines or chemokines following T. muris infection and whether divergence of the innate response could explain differentially polarized adaptive immune responses in resistant and susceptible mice. Increased expression of mRNA for the proinflammatory cytokines gamma interferon (IFN-gamma) and tumor necrosis factor and the chemokine CCL2 (MCP-1) were seen after infection of susceptible and resistant strains, with the only difference in expression being a delayed increase in CCL2 in BALB/c IEC. These increases were ablated in MyD88-/- mice, and NF-kappaB p65 was phosphorylated in response to T. muris excretory/secretory products in the epithelial cell line CMT-93, suggesting involvement of the MyD88-NF-kappaB signaling pathway in IEC cytokine expression. These data reveal that IEC respond innately to T. muris. However, the minor differences identified between resistant and susceptible mice are unlikely to underlie the subsequent development of a susceptible type 1 (IFN-gamma-dominated) or resistant type 2 (interleukin-4 [IL-4]/IL-13-dominated) adaptive immune response.     

C1q and MBL, components of the innate immune system, influence monocyte cytokine expression

It has recently been recognized that the innate immune response, the powerful first response to infection, has significant influence in determining the nature of the subsequent adaptive immune response. C1q, mannose-binding lectin (MBL), and other members of the defense collagen family of proteins are pattern recognition molecules, able to enhance the phagocytosis of pathogens, cellular debris, and apoptotic cells in vitro and in vivo. Humans deficient in C1q inevitably develop a lupus-like autoimmune disorder, and studies in C1q knockout mice demonstrate a deficiency in the clearance of apoptotic cells with a propensity for autoimmune responses. The data presented here show that under conditions in which phagocytosis is enhanced, C1q and MBL modulate cytokine production at the mRNA and protein levels. Specifically, these recognition molecules of the innate immune system contribute signals to human peripheral blood mononuclear cells, leading to the suppression of lipopolysaccharide-induced proinflammatory cytokines, interleukin (IL)-1alpha and IL-1beta, and an increase in the secretion of cytokines IL-10, IL-1 receptor antagonist, monocyte chemoattractant protein-1, and IL-6. These data support the hypothesis that defense collagen-mediated suppression of a proinflammatory response may be an important step in the avoidance of autoimmunity during the clearance of apoptotic cells.     

Pathogen interactions with endothelial cells and the induction of innate and adaptive immunity

There are over 10 trillion endothelial cells (EC) that line the vasculature of the human body. These cells not only have specialized functions in the maintenance of homeostasis within the circulation and various tissues but they also have a major role in immune function. EC also represent an important replicative niche for a subset of viral, bacterial, and parasitic organisms that are present in the blood or lymph; however, there are major gaps in our knowledge regarding how pathogens interact with EC and how this influences disease outcome. In this article, we review the literature on EC‐pathogen interactions and their role in innate and adaptive mechanisms of resistance to infection and highlight opportunities to address prominent knowledge gaps.     

The messenger between worlds: the regulation of innate and adaptive type‐2 immunity by innate lymphoid cells

Although type‐2 immune responses evolved primarily to defend against extracellular helminths, in part through the co‐opting of tissue repair and remodeling mechanisms, they are often inappropriately directed towards relatively innocuous allergens resulting in conditions including asthma, allergic rhinitis, food allergy, and atopic dermatitis. The recent discovery of group 2 innate lymphoid cells (ILC2) has increased our understanding of the initiation of these responses and the roles played by CD4⁺ T helper (Th) 2 cells in their modulation. This review focuses on the important messenger role of ILC2 in translating epithelial‐derived alarmins into downstream adaptive type‐2 responses via dendritic cells and T cells, with special emphasis on their roles in allergic disease.     

Fibroblastic reticular cells at the nexus of innate and adaptive immune responses

Lymphoid organs guarantee productive immune cell interactions through the establishment of distinct microenvironmental niches that are built by fibroblastic reticular cells (FRC). These specialized immune‐interacting fibroblasts coordinate the migration and positioning of lymphoid and myeloid cells in lymphoid organs and provide essential survival and differentiation factors during homeostasis and immune activation. In this review, we will outline the current knowledge on FRC functions in secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches and will discuss how FRCs contribute to the regulation of immune processes in fat‐associated lymphoid clusters. Moreover, recent evidence indicates that FRC critically impact immune regulatory processes, for example, through cytokine deprivation during immune activation or through fostering the induction of regulatory T cells. Finally, we highlight how different FRC subsets integrate innate immunological signals and molecular cues from immune cells to fulfill their function as nexus between innate and adaptive immune responses.     

Characterization of virus-primed CD8+ T cells with a type 1 cytokine profile

Infection with lymphocytic chorlomeningitis virus is associatedwith marked polyclonal activation of the CD8⁺ T cell subpopulation.In this report the cytokine production of virus-activated Tcells is analyzed and the producing cells subset is characterizedphenotypically. CoinciB. A. Askonasding with other parametersof cell-mediated immunity, splenic T cells appear which areable to release high amounts of IFN-, but not IL-5, IL-10 ortumor necrosis factor- upon short-term stimulation with anti-CD3in vitro. A similar profile is observed analyzing T cells takenfrom an inflammatory site. Phenotypically, the main cytokine-producingcell subset is found to be CD8⁺ cells targeted for homing toinflammatory sites (VLA-4^hiL-selectin^lo) of which 30–40%were positive by intracellular staining for IFN-. This subsetalso contains all T cells with a cytotoxic potential as measuredby redirected killing. An enhanced cytotoxic potential as wellas an increased capacity to produce IFN- is observed for atleast 2 months after infection and cell sorting analysis revealedthat this could be ascribed to a long-standing increase in thefrequency of CD8⁺Pgp-1^hi cells. Therefore, these results demonstratethat systemic virus infection may exert marked perturbationof the CD8⁺ T cell population resulting in generation of a long-livedsubset of primed cells with important effector potential.     

Regulation of adaptive immune responses by innate cells expressing NK markers and antigen-transporting macrophages

A continuing theme of work done in our laboratory involves regulation of adaptive immune response by innate cells, in general, and immuneregulation by natural killer (NK) and NKT cells, in particular. Studies include work with the lung and the eye. In addition to immune surveillance of tumor cells, the NK cell is often associated with secreting cytokines that contribute to the creation of microenvironments conducive to Th1 responses and with defense mechanisms that lessen the initial infecting viral load. Reported studies show that the NKT cells support both T helper cell responses (type 1 and 2), as well as their being absolutely central to the development of antigen-specific T-regulatory cells involved in peripheral tolerance. Because of the multifunctional capabilities of the NKT cell, we propose that yet another cell, such as the antigen-presenting cell (APC), may influence the effector pathway of the NKT cell. We postulate that the APC that transports the antigen from the entry environment provides both trafficking and activation signals for innate cells in the secondary lymphoid organs. Evidence is presented that macrophage-derived signals selectively recruit NKT cells and bias their cytokine synthesis. Data imply that, just as occurs in immune inflammation, a collection of innate and adaptive immune cells interact within the secondary lymphoid tissue to generate antigen-specific tolerance in the periphery.     

Plasmacytoid dendritic cells act as the most competent cell type in linking antiviral innate and adaptive immune responses

Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies, pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exatnining the functional and antiviral properties of in vivo pDC plasticity. Cellular ＆ Molecular Immunology. 2005;2（6）：411- 417.     

Dendritic cells and complement: at the cross road of innate and adaptive immunity

The interaction between different components of the immune system plays a pivotal role in the overall development of immune responses. Dendritic cells (DCs) and complement are essential components of innate immunity. They have been shown to be relevant both in the induction of adaptive immune responses and in maintenance of tolerance. However, hyperactivity of these systems has also been demonstrated to be detrimental in various disease states. Despite increased insight into dendritic cell biology, relatively little is known about possible interactions between dendritic cells and complement. This review focuses on novel findings, which have started to shed light on these intriguing components of the innate immune system.     

Dendritic cells and airway epithelial cells at the interface between innate and adaptive immune responses

Because they can recognize and sample inhaled allergens, dendritic cells (DC) have been shown to be responsible for the initiation and maintenance of adaptive Th2 responses in asthma. It is increasingly clear that DC functions are strongly influenced by a crosstalk with neighboring cells like epithelial cells. Whereas the epithelium was initially considered only as a barrier, it is now seen as a central player in controlling the function of lung DCs through release of innate cytokines-promoting Th2 responses. Clinically relevant allergens, as well as known environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells and DC. A better understanding of these interactions might lead to a better prevention and ultimately to new treatments for asthma.