Soluble ST2 suppresses the effect of interleukin-33 on lung type 2 innate lymphoid cells

Type 2 innate lymphoid cells (ILC2) in lungs produce interleukin (IL)-5 and IL-13 in response to IL-33 and may contribute to the development of allergic diseases such as asthma. However, little is known about negative regulators and effective inhibitors controlling ILC2 function. Here, we show that soluble ST2, a member of the IL-1 receptor family, suppresses the effect of IL-33 on lung ILC2 in vitro. Stimulation with IL-33 to naïve ILC2 induced morphological change and promoted cell proliferation. In addition, IL-33 upregulated expression of cell surface molecules including IL-33 receptor and induced production of IL-5 and IL-13, but not IL-4. Pretreatment with soluble ST2 suppressed IL-33-mediated responses of ILC2. The results suggest that soluble ST2 acts as a decoy receptor for IL-33 and protects ILC2 from IL-33 stimulation.     

Control of pathogens and microbiota by innate lymphoid cells

Innate lymphoid cells (ILCs) are the innate counterpart of T cells. Upon infection or injury, ILCs react promptly to direct the developing immune response to the one most adapted to the threat facing the organism. Therefore, ILCs play an important role early in resistance to infection, but also to maintain homeostasis with the symbiotic microbiota following perturbations induced by diet and pathogens. Such roles of ILCs have been best characterized in the intestine and lung, mucosal sites that are exposed to the environment and are therefore colonized with diverse but specific types of microbes. Understanding the dialogue between pathogens, microbiota and ILCs may lead to new strategies to re-inforce immunity for prevention, vaccination and therapy.     

Molecular characteristics and possible functions of innate lymphoid cells in the uterus and gut

With the discovery of innate lymphoid cells (ILCs), which are especially enriched in barrier surfaces, the family of innate lymphocytes has grown. A unique characterization of these cells can provide a phenotypical definition of ILCs and their specific functions in different tissue environments. Although ILCs are part of the innate immune system, they are derived from lymphoid lineages lacking rearranged antigen-specific and pattern-recognition receptors. The International Union of Immunological Societies (IUIS) favors the notion that ILCs can be generally divided into five main groups, namely, NK cells, ILC1s, ILC2s, ILC3s and LTi cells. These cells can be specifically stimulated by environmental and pathogen-derived signals. Upon stimulation, ILCs can rapidly secrete a wide range of soluble cytokines that can modulate the functions of effector cells. Over the last decade, ILCs, especially helper ILCs, which do not include NK cells, have been recognized to be a crucial cell type involved in integrating diverse host immune responses. Recently, emerging research has shown that helper ILCs also play a critical role in promoting tissue restoration and immune responses at barrier surfaces. Notably, helper ILCs act as a double-edged sword, being involved in the inflammatory and reparative responses during homeostasis and disease. Therefore, in this review, we summarize the current findings regarding the molecular characteristics and tissue-specific effector functions of helper ILCs in the uterus during physiological and pathological pregnancy and in the intestine during homeostasis and inflammation.     

Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells

The lymphotoxin (LT)-pathway is a unique constituent branch of the Tumor Necrosis Superfamily (TNFSF). Use of LT is a critical mechanism by which fetal innate lymphoid cells regulate lymphoid organogenesis. Within recent years, adult innate lymphoid cells have been discovered to utilize this same pathway to regulate IL-22 and IL-23 production for host defense. Notably, genetic studies have linked polymorphisms in the genes encoding LTα to several phenotypes contributing to metabolic syndrome. The role of the LT-pathway may lay the foundation for a bridge between host immune response, microbiota, and metabolic syndrome. The contribution of the LT-pathway to innate lymphoid cell function and metabolic syndrome will be visited in this review.     

Development and regulation of RORγt innate lymphoid cells

RORγt⁺ innate lymphoid cells (ILCs), or ILC3, play a fundamental role in the development of lymphoid tissues, as well as in homeostasis and defence of mucosal tissues. These cells produce IL-22, IL-17A and LTα1β2, key cytokines for the activation of epithelial defences and the recruitment of polymorphonuclear phagocytes. In the absence of ILC3, the early defence to infection and resistance to injury are compromised. Given the importance of ILC3 in mucosal immunity, significant efforts are made to discover their multiple functions and decipher their mode of action and regulation.     

Innate Lymphoid Cells Play a Pathogenic Role in Pericarditis

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Innate lymphoid cells and gastrointestinal disease

Innate lymphoid cells (ILCs) are a group of innate immune cells, which constitute the first line of defense in the immune system, together with skin and mucous membrane. ILCs also play an important role in maintaining the homeostasis of the body, particularly in the complex and diverse environment of the intestine. ILCs respond to different microenvironments, maintaining homeostasis directly or indirectly through cytokines. As a result, ILCs, with complex and pleiotropic characteristics, are associated with many gastrointestinal diseases. Their ability of transition among those subgroups makes them function as both promoting and inhibiting cells, thus affecting homeostasis and disease progressing to either alleviation or deterioration. With these special characteristics, ILCs theoretically can be used in the new generation of immunotherapy as an alternative and supplement to current tumor therapy. Our review summarizes the characteristics of ILCs with respect to category, function, and the relationship with intestinal homeostasis and gastrointestinal diseases. In addition, potential tumor immunotherapies involving ILCs are also discussed to shed light on the perspectives of immunotherapy.     

Th2与ILC2细胞在哮喘模型中的数量及产生细胞因子的比较研究

目的比较过敏原依赖和非依赖性哮喘模型中2型辅助性T细胞(Th2 cell)和固有淋巴样2型细胞(type 2innate lymphoid cell,ILC2)的功能。方法滴鼻法制备过敏原卵清蛋白(ovalbumin,OVA)和上皮源性细胞因子(IL-25、IL-33)诱导的亚急性和慢性哮喘小鼠模型。收集小鼠肺泡灌洗液(bronchoalvelar lavage fluid,BALF)进行细胞计数;取左肺进行石蜡包埋、切片和HE染色;右肺行流式细胞术,以分析在不同时间点各组小鼠Th2细胞和ILC2细胞数目和占肺组织总细胞比例,并对Th2型细胞因子的来源进行分析。结果与生理盐水组相比,各实验组BALF中总细胞数明显增加; HE染色可见OVA、IL-25和IL-33均可诱导哮喘典型病理学改变;各实验组肺组织中Th2细胞与ILC2细胞均明显上升,数量上以Th2细胞为主,两者均可产生Th2型细胞因子IL-5和IL-13,且以Th2细胞为主。而在致哮喘样改变、促进Th2细胞和ILC2细胞在小鼠肺部聚集等方面,以IL-33的效应最强。结论在过敏原OVA和非过敏原IL-25、IL-33诱导的哮喘模型中,Th2型细胞因子主要来源均为Th2细胞,提示Th2细胞在哮喘的发生、发展中起到主要作用。IL-33可能是过敏性和非过敏性哮喘患者个体化治疗的潜在靶点。     

髓样分化蛋白-2在天然免疫中的作用

Toll样受体 (Toll likereceptor ,TLR)家族作为模式识别受体 ,在天然免疫中具有重要作用。髓样分化蛋白 2 (myeloiddifferentialprotein 2 ,MD 2 )可能含有两个相对独立的功能结构域 ,既能与Toll样受体家族中的TLR4、TLR2结合 ,也能与多种配体结合 (包括lipopolysaccharide ,LPS)。这种特殊的结构可能与其三方面的主要功能有关 :(1)MD 2与TLR4结合 ,赋予TLR4对各种配体 (包括LPS)的反应性 ;(2 )MD 2与TLR2结合 ,赋予TLR2对LPS的反应性 ,并增强TLR2对细菌及其胞壁成分的反应性 ;(3)MD 2能促进TLR4和TLR2的表达 ,并且与TLR4在细胞内的分布密切相关。这表明MD 2可以通过两种方式直接或间接调控TLRs的功能 :与TLR2 /TLR4结合 ,或调控TLR2 /TLR4的表达与分布。因而MD 2不仅仅是TLR4的辅助分子 ,而且还是天然免疫中的调控分子 ,可能在感染、炎症、免疫等病理生理过程中具有更广泛的生物学功能     

RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity

Viral infection is detected by cellular sensors as foreign nucleic acid and initiates innate antiviral responses, including the activation of type I interferon (IFN) and proinflammatory cytokines. Recent advances in cytoplasmic virus sensors highlight their essential role in the induction of innate immunity. Moreover, it is intriguing to understand how they can discriminate innate RNA from viral foreign RNA. In this mini-review, we focus on these cytoplasmic virus sensors, termed retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), and discuss their function in the innate immune system.     

Regulation of RLR-mediated innate immune signaling--it is all about keeping the balance

The current view of cytoplasmic RNA-mediated innate immune signaling involves the differential activation of the RNA helicases retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology-2 (LGP2) by distinct RNA viruses. RIG-I, MDA5 and LGP2 form the RIG-I like receptor family (RLR). Since the initial characterization of the RLRs rapid progress has been made in the understanding of the molecular mechanisms that upon virus infection lead to the activation of downstream signaling cascades and the subsequent induction of type I interferon (IFN) and proinflammatory cytokines by these receptors. However, antiviral responses must be tightly regulated in order to prevent uncontrolled production of type I IFN that might have deleterious effects on the host. Exploring the structural and molecular mechanisms that underlie RLR signaling thus was accompanied by the discovery of how RLR-dependent antiviral responses are modulated. This article summarizes the current understanding of endogenous regulation in RLR signaling by various intrinsic molecules that exert their regulatory function in both the steady state or upon viral infection by targeting multiple steps of the signaling cascade.     

Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses

RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate immune responses. RLR signaling culminates in the activation of the protein kinase TBK1, which mediates phosphorylation and nuclear translocation of IRF3 that regulates expression of type I interferon genes. Here, we found that Nucleoporin 93 (Nup93), components of nuclear pore complex (NPC), plays an important role in RLR-mediated antiviral responses. Nup93-deficient RAW264.7 macrophage cells exhibited decreased expression of Ifnb1 and Cxcl10 genes after treatment with a synthetic RLR agonist stimulation as well as Newcastle Disease Virus infection. Silencing Nup93 in murine primary macrophages and embryonic fibroblasts also resulted in reduced expression of these genes. IRF3 nuclear translocation during RLR signaling was impaired in Nup93-deficient RAW264.7 cells. Notably, the activation of TBK1 during RLR signaling was also decreased in Nup93-deficient cells. We found that Nup93 formed a complex with TBK1, and Nup93 overexpression enhanced TBK1-mediated IFNβ promoter activation. Taken together, our findings suggest that Nup93 regulates antiviral innate immunity by enhancing TBK1 activity and IRF3 nuclear translocation.     

A possible mechanism of intravesical BCG therapy for human bladder carcinoma: involvement of innate effector cells for the inhibition of tumor growth

Intravesical bacillus Calmette-Guerin (BCG) therapy is considered the most successful immunotherapy against solid tumors of human bladder carcinoma. To determine the actual effector cells activated by intravesical BCG therapy to inhibit the growth of bladder carcinoma, T24 human bladder tumor cells, expressing very low levels of class I MHC, were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs) with live BCG. The proliferation of T24 cells was markedly inhibited when BCG-infected dendritic cells (DCs) were added to the culture although the addition of either BCG or uninfected DCs alone did not result in any inhibition. The inhibitory effect was much stronger when the DCs were infected with live BCG rather than with heat-inactivated BCG. The live BCG-infected DCs secreted TNF-α and IL-12 within a day and this secretion continued for at least a week, while the heat-inactivated BCG-infected DCs secreted no IL-12 and little TNF-α. Such secretion of cytokines may activate innate alert cells, and indeed NKT cells expressing IL-12 receptors apparently proliferated and were activated to produce cytocidal perforin among the PBMCs when live BCG-infected DCs were externally added. Moreover, depletion of γδ T-cells from PBMCs significantly reduced the cytotoxic effect on T24 cells, while depletion of CD8β cells did not affect T24 cell growth. Furthermore, the innate effectors seem to recognize MICA/MICB molecules on T24 via NKG2D receptors. These findings suggest the involvement of innate alert cells activated by the live BCG-infected DCs to inhibit the growth of bladder carcinoma and provide a possible mechanism of intravesical BCG therapy.     

NK cells require type I IFN receptor for antiviral responses during genital HSV-2 infection

Type I interferon (IFN) signalling, NK cells and NK cell-derived IFN-γ are critical in the early control of genital HSV-2 infection. We have recently reported that NK cells are the source of early IFN-γ in the genital tract in response to HSV-2. However, the response of NK cells to genital HSV-2 infection is not well defined in the context of type I IFN signalling. Here we show that HSV-2 replication was significantly higher in mice deficient in the type I IFN receptor or NK cells compared to wild type controls. There was no detectable IFN-γ production in the genital washes from IFN-α/βR^−/− mice or NK cell depleted mice in response to HSV-2 infection compared to control mice. Absence of the type I IFN receptor does not alter homing of NK cells to the genital mucosa. Moreover, the absence of IL-12 had no significant effect on NK cell-derived IFN-γ. Surprisingly, IFN-α/βR^−/− mice had more IL-15 positive cells in the genital mucosa in response to HSV-2 infection compared to control mice. We then examined the expression of IL-15 receptors on NK cells. There was no significant differences in the levels of IL-15 receptor expression on NK cells from IFN-α/βR^−/− or control mice. Our data clearly suggest that type I IFN receptor signalling is essential for NK cell activation in response to genital HSV-2 infection, and propose that NK cell activation by IL-15 may involve type I IFNs.     

Role of type 2 innate lymphoid cell and its related cytokines in tumor immunity

Type 2 innate lymphoid cells (ILC2s) have multiple functions that can respond to allergic diseases, parasite infection, metabolic homeostasis, tissue repair, and adipose metabolism homeostasis. In these diseases, ILC2s can be activated by various inflammatory cytokines released by damaged cells. Activated ILC2s produce different type 2 cytokines, including interleukin (IL)-4, IL-5, IL-9, and IL-13, which involved in the pathogenesis of many diseases. In recent years, the relationship between ILC2s and tumor diseases has attracted more and more attention. The role of ILC2s in tumor immunity depends on its surface molecules and cytokine context. This review aims to conclude tumorigenic and antitumorigenic roles of ILC2s, and the characters of ILC2s-related cytokines in tumor diseases to provide a comprehensive overview of the impact of ILC2s in tumor immunity.     

Brain heterogeneity leads to differential innate immune responses and modulates pathogenesis of viral infections

The central nervous system (CNS) is a highly complex organ with highly specialized cell subtypes. Viral infections often target specific structures of the brain and replicate in certain regions. Studies in mice deficient in type I Interferon (IFN) receptor or IFN-β have highlighted the importance of the type I IFN system against viral infections and non-viral autoimmune disorders in the CNS. Direct antiviral effects of type I IFNs appear to be crucial in limiting early spread of a number of viruses in CNS tissues. Increased efforts have been made to characterize IFN expression and responses in the brain. In this context, it is important to identify cells that produce IFN, decipher pathways leading to type I IFN expression and to characterize responding cells. In this review we give an overview about region specific aspects that influence local innate immune responses. The route of entry is critical, but also the susceptibility of different cell types, heterogeneity in subpopulations and micro-environmental cues play an important role in antiviral responses.Recent work has outlined the tremendous importance of type I IFNs, particularly in the limitation of viral spread within the CNS. This review will address recent advances in understanding the mechanisms of local type I IFN production and response, in the particular context of the CNS.