A critical review of the roles of host lactoferrin in immunity

Lactoferrin (Lf) is an essential element of innate immunity, which refers to antigen-nonspecific defense mechanisms that a host uses immediately or within hours after exposure to an antigen. Following infection, Lf is released from neutrophils (PMNs) in blood and inflamed tissues and, such as other soluble pattern-recognition receptors of the innate immunity, Lf recognizes unique microbial molecules called pathogen-associated molecular patterns (PAMPs): LPS from the gram-negative cell wall and bacterial unmethylated CpG DNA. However, unlike classical PAMPs receptors involved in the activation of immune cells, Lf may act either as a competitor for these receptors or as a partner molecule, depending on the physiological status of the organism. These immunomodulatory properties are explained by the ability of Lf to interact with proteoglycans and receptors on the surface of mammalian cells: cells of the innate (NK cells, neutrophils, macrophages, basophils, neutrophils and mast cells) and adaptive [lymphocytes and antigen-presenting cells (APCs)] immune systems, and also epithelial and endothelial cells. Through these interactions, Lf is able to modulate the migration, maturation and functions of immune cells, and thus to influence both adaptive and innate immunities. The understanding of the roles of the host-expressed Lf in immunity comes from in vivo and in vitro studies with exogenous Lf which, although informative, rarely reflect the pathological, or non-pathological, conditions in the organism. In this review, the data from the literature will be critically analyzed in order to present a real picture of the regulatory roles of host Lf in immunity.     

Regulated MIP-3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity

Human intestinal epithelial cells secrete an array of chemokines known to signal the trafficking of neutrophils and monocytes important in innate mucosal immunity. We hypothesized that intestinal epithelium may also have the capacity to play a role in signaling host adaptive immunity. The CC chemokine macrophage inflammatory protein (MIP)-3alpha/CCL20 is chemotactic for immature dendritic cells and CD45RO(+) T cells that are important components of the host adaptive immune system. In these studies, we demonstrate the widespread production and regulated expression of MIP-3alpha by human intestinal epithelium. Several intestinal epithelial cell lines were shown to constitutively express MIP-3alpha mRNA. Moreover, MIP-3alpha mRNA expression and protein production were upregulated by stimulation of intestinal epithelial cells with the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-1alpha or in response to infection with the enteric bacterial pathogens Salmonella or enteroinvasive Escherichia coli. In addition, MIP-3alpha was shown to function as a nuclear factor-kappaB target gene. In vitro findings were paralleled in vivo by increased expression of MIP-3alpha in the epithelium of cytokine-stimulated or bacteria-infected human intestinal xenografts and in the epithelium of inflamed human colon. Mucosal T cells, other mucosal mononuclear cells, and intestinal epithelial cells expressed CCR6, the cognate receptor for MIP-3alpha. The constitutive and regulated expression of MIP-3alpha by human intestinal epithelium is consistent with a role for epithelial cell-produced MIP-3alpha in modulating mucosal adaptive immune responses.     

Regulation of dendritic cell differentiation and function by estrogen receptor ligands

Estrogen receptor (ER) ligands can modulate innate and adaptive immunity and hematopoiesis, which may explain the clear sex differences in immune responses during autoimmunity, infection or trauma. Dendritic cells (DC) are antigen presenting cells important for initiation of innate and adaptive immunity, as well as immune tolerance. DC progenitors and terminally differentiated DC express ER, indicating the ER ligands may regulate DC at multiple developmental and functional stages. Although there are profound differences in innate immunity between males and females or upon systemic imposition of sex hormones, studies are just beginning to link these differences to DC. Our and others studies demonstrate that estradiol and other ER ligands regulate the homeostasis of bone marrow myeloid and lymphoid progenitors of DC, as well as DC differentiation mediated by GM-CSF and Flt3 Ligand. Since DC have a brief lifespan, these data suggest that relatively short exposures to ER ligands in vivo will alter DC numbers and intrinsic functional capacity related to their developmental state. Studies in diverse experimental models also show that agonist and antagonist ER ligands modulate DC activation and production of inflammatory mediators. These findings have implications for human health and disease since they suggest that both DC development and functional capacity will be responsive to the physiological, pharmacological and environmental ER ligands to which an individual is exposed in vivo.     

HMGB1, an alarmin promoting HIV dissemination and latency in dendritic cells

Dendritic cells (DCs) initiate immune responses by transporting antigens and migrating to lymphoid tissues to initiate T-cell responses. DCs are located in the mucosal surfaces that are involved in human immunodeficiency virus (HIV) transmission and they are probably among the earliest targets of HIV-1 infection. DCs have an important role in viral transmission and dissemination, and HIV-1 has evolved different strategies to evade DC antiviral activity. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein that can act as an alarmin, a danger signal to alert the innate immune system for the initiation of host defense. It is the prototypic damage-associated molecular pattern molecule, and it can be secreted by innate cells, including DCs and natural killer (NK) cells. The fate of DCs is dependent on a cognate interaction with NK cells, which involves HMGB1 expressed at NK–DC synapse. HMGB1 is essential for DC maturation, migration to lymphoid tissues and functional type-1 polarization of naïve T cells. This review highlights the latest advances in our understanding of the impact of HIV on the interactions between HMGB1 and DCs, focusing on the mechanisms of HMGB1-dependent viral dissemination and persistence in DCs, and discussing the consequences on antiviral innate immunity, immune activation and HIV pathogenesis.     

Apoptotic Neutrophils Augment the Inflammatory Response to Mycobacterium tuberculosis Infection in Human Macrophages

Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages. We show that Mtb infection exerts a potent proinflammatory activation of human macrophages with enhanced gene activation and release of proinflammatory cytokines and that this response was augmented by apoptotic neutrophils. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response contributing to the early control of Mtb infection.     

Interactions of DC-SIGN with Mac-1 and CEACAM1 regulate contact between dendritic cells and neutrophils

Early during infection neutrophils are the most important immune cells that are involved in killing of pathogenic bacteria and regulation of innate immune responses at the site of infection. It has become clear that neutrophils also modulate adaptive immunity through interactions with dendritic cells (DCs) that are pivotal in the induction of T cell responses. Upon activation, neutrophils release TNF-alpha and induce maturation of DCs that enables these antigen-presenting cells to stimulate T cell proliferation and to induce T helper 1 polarization. DC maturation by neutrophils also requires cellular interactions that are mediated by binding of the DC-specific receptor DC-SIGN to Mac-1 on the neutrophil. Here, we demonstrate that also CEACAM1 is an important ligand for DC-SIGN on neutrophils. Binding of DC-SIGN to both CEACAM1 and Mac-1 is required to establish cellular interactions with neutrophils. DC-SIGN is a C-type lectin that has specificity for Lewis(x), and we show that DC-SIGN mediates binding to CEACAM1 through Lewis(x) moieties that are specifically expressed on CEACAM1 derived from neutrophils. This indicates that glycosylation-driven binding of both Mac-1 and CEACAM1 to DC-SIGN is essential for interactions of neutrophils with DCs and enables neutrophils to modulate T cell responses through interactions with DCs.     

自然杀伤细胞和树突状细胞相互作用

近年来,自然杀伤(NK)细胞和树突状细胞(DCs)的相互作用逐渐成为免疫学领域的一个研究热点。越来越多的实验表明,两种细胞可通过细胞-细胞接触并分泌细胞因子在炎症组织和次级淋巴结中相互作用,在机体抗肿瘤、抗病毒及抗移植排斥等效应中发挥重要作用。现对NK细胞和DCs相互作用及生物学意义等方面的研究进展进行综述。     

Involvement of NK cells against tumors and parasites

Host resistance against pathogens depends on a complex interplay of innate and adaptive immune mechanisms. Acting as an early line of defence, the immune system includes activation of neutrophils, tissue macrophages, monocytes, dendritic cells, eosinophils and natural killer (NK) cells. NK cells are lymphoid cells that can be activated without previous stimulation and are therefore like macrophages in the first line of defence against tumor cells and a diverse range of pathogens. NK cells mediate significant activity and produce high levels of proinflammatory cytokines in response to infection. Their cytotoxicity production is induced principally by monocyte-, macrophage- and dendritic cell-derived cytokines, but their activation is also believed to be cytokine-mediated. Recognition of infection by NK cells is accomplished by numerous activating and inhibitory receptors on the NK cells' surface that selectively trigger the cytolytic activity in a major histocompability complex-independent manner. NK cells have trypanocidal activity of fibroblast cells and mediate direct destruction of extracellular epimastigote and trypomastigote forms of T. cruzi and T. lewisi in vitro; moreover, they kill plasmodia-infected erythrocytes directly through cell-cell interaction. This review provides a more detailed analysis of how NK cells recognize and respond to parasites and how they mediate cytotoxicity against tumor cells. Also the unique role of NK cells in innate immunity to infection and the relationship between parasites and carcinogenesis are discussed.     

An unexpected role for hypoxic response: oxygenation and inflammation

The eradication of invading microorganisms depends initially on innate immunity mechanisms that preexist in all individuals and act within minutes of infection. Pathogen spread is often countered by an inflammatory response that recruits more effector molecules and cells of the innate immune system from local blood vessels, while inducing clotting farther downstream so that pathogens cannot spread throughout the blood. If a microorganism crosses an epithelial barrier and begins to replicate in the tissues of the host, it is, in some cases, immediately recognized by the mononuclear phagocytes, or macrophages, that reside in tissues. Macrophages mature continuously from circulating monocytes that leave the circulation to migrate into tissues throughout the body. The second major family of phagocytes, the neutrophils or polymorphonuclear leukocytes (PMNs) are short-lived cells that are abundant cells in the blood but are not present in healthy tissues. Both phagocytic cell types play a key role in innate immunity because they can recognize, ingest and destroy many pathogens without the aid of an adaptive immune response. This infiltration of neutrophils and later macrophages to the site of bacterial infection is tightly linked with the need of these immune defense cells to respond to the tissue microenvironment.     

An Unexpected Role for Hypoxic Response: Oxygenation and Inflammation

The eradication of invading microorganisms depends initially on innate immunity mechanisms that preexist in all individuals and act within minutes of infection. Pathogen spread is often countered by an inflammatory response that recruits more effector molecules and cells of the innate immune system from local blood vessels, while inducing clotting farther downstream so that pathogens cannot spread throughout the blood. If a microorganism crosses an epithelial barrier and begins to replicate in the tissues of the host, it is, in some cases, immediately recognized by the mononuclear phagocytes, or macrophages, that reside in tissues. Macrophages mature continuously from circulating monocytes that leave the circulation to migrate into tissues throughout the body. The second major family of phagocytes, the neutrophils or polymorphonuclear leukocytes (PMNs) are short-lived cells that are abundant cells in the blood but are not present in healthy tissues. Both phagocytic cell types play a key role in innate immunity because they can recognize, ingest and destroy many pathogens without the aid of an adaptive immune response. This infiltration of neutrophils and later macrophages to the site of bacterial infection is tightly linked with the need of these immune defense cells to respond to the tissue microenvironment.     

IL-4 Attenuates Th1-Associated Chemokine Expression and Th1 Trafficking to Inflamed Tissues and Limits Pathogen Clearance

Interleukin 4 (IL-4) plays a central role in the orchestration of Type 2 immunity. During T cell activation in the lymph node, IL-4 promotes Th2 differentiation and inhibits Th1 generation. In the inflamed tissue, IL-4 signals promote innate and adaptive Type-2 immune recruitment and effector function, positively amplifying the local Th2 response. In this study, we identify an additional negative regulatory role for IL-4 in limiting the recruitment of Th1 cells to inflamed tissues. To test IL-4 effects on inflammation subsequent to Th2 differentiation, we transiently blocked IL-4 during ongoing dermal inflammation (using anti-IL-4 mAb) and analyzed changes in gene expression. Neutralization of IL-4 led to the upregulation of a number of genes linked to Th1 trafficking, including CXCR3 chemokines, CCL5 and CCR5 and an associated increase in IFNγ, Tbet and TNFα genes. These gene expression changes correlated with increased numbers of IFNγ-producing CD4+ T cells in the inflamed dermis. Moreover, using an adoptive transfer approach to directly test the role of IL-4 in T cell trafficking to the inflamed tissues, we found IL-4 neutralization led to an early increase in Th1 cell recruitment to the inflamed dermis. These data support a model whereby IL-4 dampens Th1-chemokines at the site of inflammation limiting Th1 recruitment. To determine biological significance, we infected mice with Leishmania major, as pathogen clearance is highly dependent on IFNγ-producing CD4+ T cells at the infection site. Short-term IL-4 blockade in established L. major infection led to a significant increase in the number of IFNγ-producing CD4+ T cells in the infected ear dermis, with no change in the draining LN. Increased lymphocyte influx into the infected tissue correlated with a significant decrease in parasite number. Thus, independent of IL-4''s role in the generation of immune effectors, IL-4 attenuates lymphocyte recruitment to the inflamed/infected dermis and limits pathogen clearance.     

Neutrophils sustain effective CD8(+) T-cell responses in the respiratory tract following influenza infection

Neutrophils have an important role in early host protection during influenza A virus infection. Their ability to modulate the virus-specific adaptive immune response is less clear. Here, we have used a mouse model to examine the impact of neutrophils on CD8(+) T-cell responses during influenza virus infection. CD8(+) T-cell priming, expansion, migration, cytokine secretion and cytotoxic capacity were investigated in the virus-infected airways and secondary lymphoid organs. To do this, we utilised a Ly6G-specific monoclonal antibody (mAb; 1A8) that specifically depletes neutrophils in vivo. Neutrophil depletion early after infection with influenza virus strain HKx31 (H3N2) did not alter influenza virus-derived antigen presentation or na?ve CD8(+) T-cell expansion in the secondary lymphoid organs. Trafficking of virus-specific CD8(+) T cells into the infected pulmonary airways was also unaltered. Instead, early neutropenia reduced both the overall magnitude of influenza virus-specific CD8(+) T cells, together with impaired cytokine production and cytotoxic effector function. Therefore, neutrophils are important participants in anti-viral mechanisms that sustain effective CD8(+) T-cell responses in the respiratory tract of influenza virus-infected mice.     

Shaping immune responses through the activation of dendritic cells–P2 receptors

Dendritic cells (DCs) activate and shape the adaptive immune response by capturing antigens, migrating to peripheral lymphoid organs where naïve T cells reside, expressing high levels of MHC and costimulatory molecules and secreting cytokines and chemokines. DCs are endowed with a high degree of functional plasticity and their functions are tightly regulated. Besides initiating adaptive immune responses, DCs play a key role in maintaining peripheral tolerance toward self-antigens. On the basis of the information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. A wide variety of signals from neighbouring cells affecting DC functional activity have been described. Here we will discuss the complex role of extracellular nucleotides in the regulation of DC function and the role of P2 receptors as possible tools to manipulate immune responses.     

Application of proteomics to neutrophil biology

Polymorphonuclear leukocytes or neutrophils are a primary effector cell of the innate immune system and contribute to the development of adaptive immunity. Neutrophils participate in both the initiation and resolution of inflammatory responses through a series of highly coordinated molecular and phenotypic changes. To accomplish these changes, neutrophils express numerous receptors and use multiple overlapping and redundant signal transduction pathways. Dysregulation of the activation or resolution pathways plays a role in a number of human diseases. A comprehensive understanding of the regulation of neutrophil responses can be provided by high throughput proteomic technologies and sophisticated computational analysis. The first steps in the application of proteomics to understanding neutrophil biology have been taken. Here we review the application of expression, structural, and functional proteomic studies to neutrophils. Although defining the complex molecular events associated with neutrophil activation is in the early stages, the data generated to date suggest that proteomic technologies will dramatically enhance our understanding of neutrophil biology.     

Th1 cell-mediated resistance to cutaneous infection with Leishmania major is independent of P- and E-selectins

Studies in several models of inflammation have underscored the importance of P- and E-selectins in the migration of T cells to inflamed tissues. However, the role of the endothelial selectins in infection-induced cutaneous inflammation and host-protective immunity has not been investigated. In this study, we demonstrate that CD4(+) T cells recruited to the cutaneous compartment during infection with Leishmania major express P- and E-selectin ligands. Furthermore, expression of P- and E-selectin ligands correlates with activated Leishmania-specific Th1 cells and is dependent upon IL-12. To investigate the functional role of the endothelial selectins during leishmaniasis, we infected mice either singly or doubly deficient in the expression of P- and E- selectins. Mice lacking both P- and E-selectins developed significantly less inflammation at the site of a primary and secondary infection, and exhibited an impaired delayed-type hypersensitivity response. Surprisingly, the absence of the endothelial selectins had no effect on the control of parasite replication or immunity to reinfection. Thus, these data demonstrate that although the endothelial selectins contribute to the inflammatory response, they are not required for protective immunity to L. major. Moreover, these data suggest that by blocking P- and E-selectins, the immune pathology associated with cutaneous leishmaniasis might be ameliorated without compromising immunity to infection.     

Neutrophils and intracellular pathogens: beyond phagocytosis and killing

Neutrophils are not simply scavenging phagocytes that clear extracellular spaces of rapidly proliferating microbes; they are also active in the control of infections by intracellular pathogens. Several mechanisms for nonphagocytic roles of neutrophils in protective immunity have been put forth over the years but further evidence has recently been accumulating at an increasing pace. In this review, I present the evidence that suggests neutrophils are involved in pathogen shuttling into the lymphoid tissues, in antigen presentation, and in early T cell recruitment and initiation of granuloma organization. Also, a clearer view on the antimicrobial molecules that can be acquired by macrophages to enhance their antimicrobial activity is now emerging. Finally, neutrophils can adversely affect immunity against certain parasites by causing immune deviation.     

A myriad of functions and complex regulation of the CCR7/CCL19/CCL21 chemokine axis in the adaptive immune system

The chemokine receptor CCR7 and its ligands CCL19 and CCL21 control a diverse array of migratory events in adaptive immune function. Most prominently, CCR7 promotes homing of T cells and DCs to T cell areas of lymphoid tissues where T cell priming occurs. However, CCR7 and its ligands also contribute to a multitude of adaptive immune functions including thymocyte development, secondary lymphoid organogenesis, high affinity antibody responses, regulatory and memory T cell function, and lymphocyte egress from tissues. In this survey, we summarise the role of CCR7 in adaptive immunity and describe recent progress in understanding how this axis is regulated. In particular we highlight CCX-CKR, which scavenges both CCR7 ligands, and discuss its emerging significance in the immune system.     

半乳糖凝集素1的免疫功能

半乳糖凝集素为S型凝集素,因其可特异性识别β-半乳糖苷键而得名。半乳糖凝集素1是最早发现的半乳糖凝集素家族成员,它在固有免疫与适应性免疫中均发挥着重要的作用。在固有免疫中,半乳糖凝集素1调节中性粒细胞、肥大细胞、巨噬细胞的功能,进而调节免疫反应;在适应性免疫中,半乳糖凝集素1对T细胞有重要的免疫调节功能,在T细胞存活、T细胞免疫调节、T细胞免疫疾病、炎症、肿瘤发生发展及免疫逃逸中都扮演着重要的角色。