2B4 (CD244) and NK-T-B-antigen (NTB-A, CD352) are activating receptors on human natural killer (NK) cells and belong to the family of signaling lymphocyte activation molecule (SLAM)-related receptors (SRR). Engagement of these receptors leads to phosphorylation of their cytoplasmic tails and recruitment of the adapter proteins SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript-2 (EAT-2). X-linked lymphoproliferative syndrome (XLP) is a severe immunodeficiency that results from mutations in the SAP gene. 2B4 and NTB-A-mediated cytotoxicity are abrogated in XLP NK cells. To elucidate the molecular basis for this defect we analyzed early signaling events in SAP knockdown cells. Similar to XLP NK cells, knockdown of SAP in primary human NK cells leads to a reduction of 2B4 and NTB-A-mediated cytotoxicity. We found that early signaling events such as raft recruitment and receptor phosphorylation are not affected by the absence of SAP, indicating the defect in the absence of SAP is downstream of these events. In addition, knockdown of EAT-2 does not impair 2B4 or NTB-A-mediated cytotoxicity. Surprisingly, EAT-2 recruitment to both receptors is abrogated in the absence of SAP, revealing a novel cooperativity between these adapters.
natural killer cells; human; cell activation; cell surface molecules; cytotoxicity
Neutrophil extracellular traps (NETs) are beneficial antimicrobial defense structures that can help fight against invading pathogens in the host. However, recent studies reveal that NETs exert adverse effects in a number of diseases including those of the lung. Many inflammatory lung diseases are characterized with a massive influx of neutrophils into the airways. Neutrophils contribute to the pathology of these diseases. To date, NETs have been identified in the lungs of cystic fibrosis (CF), acute lung injury (ALI), allergic asthma, and lungs infected with bacteria, virus, or fungi. These microbes and several host factors can stimulate NET formation, or NETosis. Different forms of NETosis have been identified and are dependent on varying types of stimuli. All of these pathways however appear to result in the formation of NETs that contain DNA, modified extracellular histones, proteases, and cytotoxic enzymes. Some of the NET components are immunogenic and damaging to host tissue. Innate immune collectins, such as pulmonary surfactant protein D (SP-D), bind NETs, and enhance the clearance of dying cells and DNA by alveolar macrophages. In many inflammatory lung diseases, bronchoalveolar SP-D levels are altered and its deficiency results in the accumulation of DNA in the lungs. Some of the other therapeutic molecules under consideration for treating NET-related diseases include DNases, antiproteases, myeloperoxidase (MPO) inhibitors, peptidylarginine deiminase-4 inhibitors, and anti-histone antibodies. NETs could provide important biological advantage for the host to fight against certain microbial infections. However, too much of a good thing can be a bad thing. Maintaining the right balance of NET formation and reducing the amount of NETs that accumulate in tissues are essential for harnessing the power of NETs with minimal damage to the hosts.
neutrophil extracellular traps (NETs); lung inflammation; lung infection; surfactant protein D (SP-D); cystic fibrosis (CF); acute lung injury (ALI); neutrophil
A central objective in organ transplantation and the treatment or prevention of autoimmune disease is the achievement of antigen-specific immune tolerance. An additional challenge in bone marrow transplantation for the treatment of hematological malignancies is the prevention of graft-vs-host disease (GVHD) while maintaining graft-vs-tumor activity. Interestingly, CD4-CD8- (double negative, DN) T cells, which exhibit a unique antigen-specific immunoregulatory potential, appear to exhibit all of the properties to respond to these challenges. Herein, we review the therapeutic potential of immunoregulatory DN T cells in various immunopathological settings, including graft tolerance, GVHD, cancer, and autoimmunity.
graft-vs-host disease; autoimmunity; cancer; graft tolerance; immunoregulation; double negative T cells
The world's most successful intracellular bacterial pathogen, Mycobacterium tuberculosis (MTB), survives inside macrophages by blocking phagosome maturation and establishes chronic infection characterized by the formation of granulomas. Trehalose-6,6-dimycolate (TDM), the mycobacterial cord factor, is the most abundant cell wall lipid of virulent mycobacteria, is sufficient to cause granuloma formation, and has long been known to be a major virulence factor of MTB. Recently, TDM has been shown to activate the Syk-Card9 signaling pathway in macrophages through binding to the C-type lectin receptor Mincle. The Mincle-Card9 pathway is required for activation of macrophages by TDM in vitro and for granuloma formation in vivo following injection of TDM. Whether this pathway is also exploited by MTB to reprogram the macrophage into a comfortable niche has not been explored yet. Several recent studies have investigated the phenotype of Mincle-deficient mice in mycobacterial infection, yielding divergent results in terms of a role for Mincle in host resistance. Here, we review these studies, discuss possible reasons for discrepant results and highlight open questions in the role of Mincle and other C-type lectin receptors in the infection biology of MTB.
mycobacteria; cord factor; TDM; Mincle; C-type lectin receptor; tuberculosis
In the present short review, we analyze past experiments that addressed the interactions of intracellular pathogenic protozoa (Trypanosoma cruzi, Toxoplasma gondii, and Plasmodium) with host cells and the initial use of the term active penetration to indicate that a protozoan “crossed the host cell membrane, penetrating into the cytoplasm.” However, the subsequent use of transmission electron microscopy showed that, for all of the protozoans and cell types examined, endocytosis, classically defined as involving the formation of a membrane-bound vacuole, took place during the interaction process. As a consequence, the recently penetrated parasites are always within a vacuole, designated the parasitophorous vacuole (PV).
Trypanosoma cruzi; endocytosis; active penetration; phagocytosis; Chagas disease
In recent years, our understanding of the role of natural killer (NK) cells in the response to viral infection has grown rapidly. Not only do we realize viruses have many immune-evasion strategies to escape NK cell responses, but that stimulation of NK cell subsets during an antiviral response occurs through receptors seemingly geared directly at viral products and that NK cells can provide a memory response to viral pathogens. Tremendous knowledge has been gained in this area through the study of herpes viruses, but appreciation for the significance of NK cells in the response to other types of viral infections is growing. The function of NK cells in defense against poxviruses has emerged over several decades beginning with the early seminal studies showing the role of NK cells and the NK gene complex in susceptibility of mouse strains to ectromelia, a poxvirus pathogen of mice. More recently, greater understanding has emerged of the molecular details of the response. Given that human diseases caused by poxviruses can be as lethal as smallpox or as benign as Molluscum contagiosum, and that vaccinia virus, the prototypic member of the pox family, persists as a mainstay of vaccine design and has potential as an oncolytic virus for tumor therapy, further research in this area remains important. This review focuses on recent advances in understanding the role of NK cells in the immune response to poxviruses, the receptors involved in activation of NK cells during poxvirus infection, and the viral evasion strategies poxviruses employ to avoid the NK response.
natural killer cells; poxvirus; ectromelia virus; vaccinia virus; NK receptor; MHC class I; Qa-1; NKRP1
Endometriosis, a common cause of pelvic pain and female infertility, depends on the growth of vascularized endometrial tissue at ectopic sites. Endometrial fragments reach the peritoneal cavity during the fertile years: local cues decide whether they yield endometriotic lesions. Macrophages are recruited at sites of hypoxia and tissue stress, where they clear cell debris and heme-iron and generate pro-life and pro-angiogenesis signals. Macrophages are abundant in endometriotic lesions, where are recruited and undergo alternative activation. In rodents macrophages are required for lesions to establish and to grow; bone marrow-derived Tie-2 expressing macrophages specifically contribute to lesions neovasculature, possibly because they concur to the recruitment of circulating endothelial progenitors, and sustain their survival and the integrity of the vessel wall. Macrophages sense cues (hypoxia, cell death, iron overload) in the lesions and react delivering signals to restore the local homeostasis: their action represents a necessary, non-redundant step in the natural history of the disease. Endometriosis may be due to a misperception of macrophages about ectopic endometrial tissue. They perceive it as a wound, they activate programs leading to ectopic cell survival and tissue vascularization. Clearing this misperception is a critical area for the development of novel medical treatments of endometriosis, an urgent and unmet medical need.
endometriosis; alternatively activated macrophages; angiogenesis; Tie-2 expressing macrophages; iron; phagocytosis; hypoxia
Natural killer (NK) cells have been shown to play a regulatory role in sepsis. According to the current view, NK cells become activated via macrophages or dendritic cells primed by lipopolysaccharide (LPS). Recently, TLR4 gene expression was detected in human NK cells suggesting the possibility of a direct action of LPS on NK cells. In this study, effects of LPS on NK cell cytokine production and cytotoxicity were studied using highly purified human NK cells. LPS was shown to induce IFN-γ production in the presence of IL-2 in NK cell populations containing>98% CD56+ cells. Surprisingly, in the same experiments LPS decreased NK cell degranulation. No significant expression of markers related to blood dendritic cells, monocytes or T or B lymphocytes in the NK cell preparations was observed; the portions of HLA-DR-bright, CD14+, CD3+, and CD20+ cells amounted to less than 0.1% within the cell populations. No more than 0.2% of NK cells were shown to be slightly positive for surface TLR4 in our experimental system, although intracellular staining revealed moderate amounts of TLR4 inside the NK cell population. These cells were negative for surface CD14, the receptor participating in LPS recognition by TLR4. Incubation of NK cells with IL-2 or/and LPS did not lead to an increase in TLR4 surface expression. TLR4-CD56+ NK cells isolated by cell sorting secreted IFN-γ in response to LPS. Antibody to TLR4 did not block the LPS-induced increase in IFN-γ production. We have also shown that Re-form of LPS lacking outer core oligosaccharide and O-antigen induces less cytokine production in NK cells than full-length LPS. We speculate that the polysaccharide fragments of LPS molecule may take part in LPS-induced IFN-γ production by NK cells. Collectively our data suggest the existence of a mechanism of LPS direct action on NK cells distinct from established TLR4-mediated signaling.
NK cells; lipopolysaccharide; cytokine production; cytotoxicity; flow cytometry
Killer cell immunoglobulin-like receptors (KIRs) are a family of cell surface inhibitory or activating receptors expressed on natural killer cells and some subpopulations of T lymphocytes. KIR genes are clustered in the 19q13.4 region and are characterized by both allelic (high numbers of variants) and haplotypic (different numbers of genes for inhibitory and activating receptors on individual chromosomes) polymorphism. This contributes to diverse susceptibility to diseases and other clinical situations. Associations of KIR genes, as well as of genes for their ligands, with selected diseases such as psoriasis vulgaris and atopic dermatitis, rheumatoid arthritis, recurrent spontaneous abortion, and non-small cell lung cancer are discussed in the context of NK and T cell functions.
KIR genes; skin disease; rheumatoid arthritis; spontaneous abortion; cancer; viral diseases; viral infections
The clonal expansion, differentiation into effectors and establishing an immunological memory are crucial components of the adaptive immune response. Following the initial encounter with a pathogen, clonal CD8 T cell expansion yields at least two distinct populations of effector cells, short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). SLECs are the terminally differentiated cells, which play an active role in pathogen clearance and undergo apoptosis once the pathogen is eliminated. In contrast, MPECs persist and give rise to self-renewing memory cells. These memory CD8 T cells maintain a state of heightened alertness and are poised to rapidly respond and swiftly clear the pathogen upon antigen re-encounter. As one of the goals of vaccination is to induce the development of these memory CD8 T cells, understanding the cellular and molecular basis of memory cell differentiation is critical to rational vaccine design. It is clear that memory differentiation is complex and involves multiple interrelated signaling pathways. It is influenced by factors such as the strength and duration of antigen receptor signaling and concurrent exposure to cytokines. Several signaling pathways that influence T cell fate have been recently described, and many culminate in the differential expression of specific transcription factors. Unfortunately, the mechanisms underlying the coordination and confluence of these signaling pathways remain largely unknown. In this review, we will discuss the role of the phosphatidylinositol 3-kinase signaling pathway as a central signaling node, and the function of Akt as a rheostat in orchestrating the differentiation of memory CD8 T cells.
memory T cell; PI3K/Akt; mTOR; FOXO; differentiation; metabolism
Natural killer (NK) cells are involved in innate immune responses and play a major role in tumor surveillance and in defense against viruses. Human NK cells recognize human leukocyte antigen (HLA) class I molecules via surface receptors [killer immunoglobulin-like receptor (KIR) and NKG2A] delivering signals that inhibit NK cell function and kill HLA class I-deficient target cells, a frequent event in tumors or virus-infected cells. NK cell triggering is mediated by activating receptors that recognize ligands expressed primarily on tumors or virus-infected cells. NK cells play also a key role in the cure of high-risk leukemias. Thus, donor-derived “alloreactive” NK cells are fundamental effectors in adult acute myeloid leukemia and in pediatric acute lymphoblastic leukemia patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT). Alloreactive NK cells mediate killing of leukemia cells and patient’s dendritic cell, thus preventing respectively leukemic relapses and graft-vs-host responses. Cytofluorimetric analysis of KIRs expressed by NK cells allows to define the size of the alloreactive NK subset and the selection of the best potential donor. Recently, it has been shown that also the expression of activating KIRs, in particular the (C2-specific) KIR2DS1, may contribute to donor NK alloreactivity. It has also been established a correlation between the size of the alloreactive NK cell population and the clinical outcome. Notably, the alloreactive NK cells derived from donor’s hematopoietic stem cells are generated and persist in patients over time. The high survival rates of patients undergoing haploidentical HSCT highlight an important new reality in the setting of allograft performed to cure otherwise fatal leukemias. Novel approaches are in progress to further improve the clinical outcome based on the infusion of donor alloreactive NK cells either as a component of the transplanted cell population or as in vitro expanded NK cells.
natural killer cells; killer Ig-like receptors; NK alloreactivity; acute myeloid leukemia; acute lymphoblastic leukemia; haploidentical hemopoietic stem cell transplantation; graft-vs-host disease
Interleukin (IL)-10 and IL-22 are key members of the IL-10 cytokine family that share characteristic properties such as defined structural features, usage of IL-10R2 as one receptor chain, and activation of signal transducer and activator of transcription (STAT)-3 as dominant signaling mode. IL-10, formerly known as cytokine synthesis inhibitory factor, is key to deactivation of monocytes/macrophages and dendritic cells. Accordingly, pre-clinical studies document its anti-inflammatory capacity. However, the outcome of clinical trials assessing the therapeutic potential of IL-10 in prototypic inflammatory disorders has been disappointing. In contrast to IL-10, IL-22 acts primarily on non-leukocytic cells, in particular epithelial cells of intestine, skin, liver, and lung. STAT3-driven proliferation, anti-apoptosis, and anti-microbial tissue protection is regarded a principal function of IL-22 at host/environment interfaces. In this hypothesis article, hidden/underappreciated pro-inflammatory characteristics of IL-10 and IL-22 are outlined and related to cellular priming by type I interferon. It is tempting to speculate that an inherent inflammatory potential of IL-10 and IL-22 confines their usage in tissue protective therapy and beyond that determines in some patients efficacy of type I interferon treatment.
inflammation; type I interferons; interleukin-10; interleukin-22; signal transducer and activator of transcription
In a nomenclature proposal published in 2010 monocytes were subdivided into classical and non-classical cells and in addition an intermediate monocyte subset was proposed. Over the last couple of years many studies have analyzed these intermediate cells, their characteristics have been described, and their expansion has been documented in many clinical settings. While these cells appear to be in transition from classical to non-classical monocytes and hence may not form a distinct cell population in a strict sense, their separate analysis and enumeration is warranted in health and disease.
classical monocytes; non-classical monocytes; intermediate monocytes; monocyte subsets; monocyte classification
Natural killer (NK) cells are able to recognize and kill tumor cells, however whether they contribute to tumor immunosurveillance is still debated. Our previous studies demonstrated the presence of NK cells in human lung tumors. Their comparison with NK cells from non-tumoral lung tissues and with blood NK cells from the same individuals revealed a decreased expression of some NK receptors and impaired ex vivo cytotoxic functions occurring specifically in NK cells isolated from the tumor microenvironment. The aim of the present study was to characterize the transcriptional profile of such intratumoral NK cells, by comparative microarray analysis of sorted NK cells isolated from non-tumoral (Non-Tum-NK) and tumoral (Tum-NK) lung tissues of 12 Non-Small Cell Lung Cancer patients. Our results reveal a specific gene expression signature of Tum-NK cells particularly in activation processes and cytotoxicity, confirming that tumor environment induces modifications in NK cells biology. Indeed, intratumoral NK cells display higher expression levels of NKp44, NKG2A, Granzymes A and K, and Fas mRNA. A particular pattern of receptors involved in chemotaxis was also observed, with an overexpression of CXCR5 and CXCR6, and a lower expression of CX3CR1 and S1PR1 genes in Tum-NK as compared to Non-Tum-NK cells. The precise identification of the molecular pathways modulated in the tumor environment will help to decipher the role of NK cells in tumor immunosurveillance and will open future investigations to manipulate their antitumoral functions.
NK cells; lung cancer; microarray
Inflammation, in conjunction with leukocytes, plays a key role in most acute kidney injury (AKI). Non-resolving renal inflammation leads to chronic fibrosis and renal failure. Resolvin D series (RvDs) and E series (RvEs), protectins, and maresins (MaRs) are endogenous omega-3 fatty acid-derived lipid mediators (LMs) that potently promote inflammation resolution by shortening neutrophil life span and promoting macrophage (Mf) non-phelogistic phagocytosis of apoptotic cells and the subsequent exit of Mfs from inflammatory tissue. 14S,21R-dihydroxy docosahexaenoic acid (14S,21R-diHDHA), a Mf-produced autacrine, reprograms Mfs to rescue vascular endothelia. RvD1, RvE1, or 14S,21R-diHDHA also switches Mfs to the phenotype that produces pro-resolving interleukin-10. RvDs or protectin/neuroprotectin D1 (PD1/NPD1) inhibits neutrophil infiltration into injured kidneys, blocks toll-like receptor -mediated inflammatory activation of Mfs and mitigates renal functions. RvDs also repress renal interstitial fibrosis, and PD1 promotes renoprotective heme-oxygenase-1 expression. These findings provide novel approaches for targeting inflammation resolution and LMs or modulation of LM-associated pathways for developing better clinical treatments for AKI.
resolvins; protectins/neuroprotectins; maresins; 14S,21R-diHDHA; inflammation-resolution; kidney-injury; fibrosis; leukocytes
Responsiveness of maturing natural killer (NK) cells to chemotactic molecules directly affect their retention and relocation in selected bone marrow (BM) microenvironment during development, as well as their localization at sites of immune response during inflammatory diseases. BM is the main site of NK cell generation, providing microenvironmental signals required to sustain cell proliferation and differentiation. Drastic changes of expression and function of several chemoattractant receptors can be observed during progression from precursor NK cells to immature and mature NK cells. Indeed, the gradual decrease of CXCR4 expression parallels the increased expression of CXCR3, CCR1, and CX3CR1 and S1P5 (Sphingosine-1-phosphate receptor 5) on mature DX5+ NK cells. The chemokine CXCL12 is produced constitutively in the BM and, acting via CXCR4, is critical for retaining immature and mature NK cell subsets in the BM. During steady-state, the maintenance of NK cells into BM parenchyma depends on the equilibrium of CXCR4 retention and S1P5 mobilizing functions, as the gradient of S1P coming from the sinusoids facilitates mature NK cell egress into circulation via S1P5, when CXCR4/CXCL12-mediated retention decreases. Chemoattractants are also key factors for the response to inflammatory or infection conditions that promote mobilization of effector NK cells from storage compartments (including BM) to sites of disease or for NK cell recruitment/response during pathological conditions that affect BM integrity, including hematopoietic malignancies. In this review, we summarize what is known about the requirement for NK cell localization and exit from BM and how chemokine-mediated functions may affect BM NK cell development and immune responses.
NK cells; chemokines; trafficking; bone marrow; egress
Natural killer (NK) cells can derive from the same precursors as B and T cells, however, to achieve lineage specificity, several transcription factors need to be activated or annulled. While a few important transcription factors have been identified for NK genesis the mechanisms of how this is achieved is far from resolved. Adding to the complexity of this, NK cells are found and potentially develop in diverse locations in vivo and it remains to be addressed if a common NK cell precursor seeds diverse niches and how transcription factors may differentially regulate NK cell commitment in distinct microenvironments. Here we will summarize some recent findings in NK cell commitment and discuss how a NK cell transcriptional network might be organized, while addressing some misconceptions and anomalies along the way.
innate lymphocytes; natural killer cells; development; pre-pro NK cells; transcription factors; differentiation; ID2; NFIL3
Despite major advances in T cell receptor (TCR) biology and structure, how peptide–MHC complex (pMHC) ligands trigger αβ TCR activation remains unresolved. Two views exist. One model postulates that monomeric TCR–pMHC ligation events are sufficient while a second proposes that TCR–TCR dimerization in cis via Cα domain interaction plus pMHC binding is critical. We scrutinized 22 known TCR/pMHC complex crystal structures, and did not find any predicted molecular Cα–Cα contacts in these crystals that would allow for physiological TCR dimerization. Moreover, the presence of conserved glycan adducts on the outer face of the Cα domain preclude the hypothesized TCR dimerization through the Cα domain. Observed functional consequences of Cα mutations are likely indirect, with TCR microclusters at the immunological synapse driven by TCR transmembrane/cytoplasmic interactions via signaling molecules, scaffold proteins, and/or cytoskeletal elements.
TCR; receptor dimerization; signal transduction; structural immunology
Granulomas represent a spectrum of inflammatory sequestration responses that may be initiated by a variety of agents, including non-infectious environmental factors and infectious microbial pathogens. Although this reaction is designed to be protective, the associated tissue injury is often responsible for a profound degree of pathology. While many of the mechanisms that sustain the development of the granuloma are enigmatic, it is accepted that the maintenance of this inflammatory process is dependent upon dynamic interactions between an inciting agent, inflammatory mediators, various immune and inflammatory cells, and structural cells of the involved tissue. The best studied of the host-dependent processes during granuloma development is the innate and adaptive immune response. The innate immune response by antigen-presenting cells [APCs; dendritic cells (DCs) and macrophages] is initiated quickly to protect from overwhelming pathogens, but with time, can also activate the adaptive immune response. APCs, essential regulators of the innate immune response, can respond to microbial ligands through Toll-like receptors (TLRs), which function in the recognition of microbial components and play an important role to link the innate and adaptive immune responses. CD4+ T helper (Th) cells are essential regulators of adaptive immune responses and inflammatory diseases. Recently, the Notch system has been shown to be an important bridge between APCs and T cell communication circuits. In the present review, we discuss recent findings that explore the mechanisms in the linkage of innate and adaptive immunity, including granulomatous formation though TLRs and Notch activation.
Notch signaling; Toll-like receptor; dendritic cell; T helper cell; innate immunity; acquired immunity
The composition of the early immune repertoire is biased with prominent expression of spontaneously arising B cell clones that produce IgM with recurrent and often autoreactive binding specificities. Amongst these naturally arising antibodies (NAbs) are IgM antibodies that specifically recognized amaged and senescent cells, often via oxidation-associated neo-determinants. These NAbs are present from birth and can be further boosted by apoptotic cell challenge. Recent studies have shown that IgM NAb to apoptotic cells can enhance phagocytic clearance, as well as suppress proinflammatory responses induced via Toll-like receptors, and block pathogenic IgG-immune complex (IC)-mediated inflammatory responses. Specific antibody effector functions appear to be involved, as these anti-inflammatory properties are dependent on IgM-mediated recruitment of the early recognition factors of complement. Clinical surveys have suggested that anti-apoptotic cell (AC) IgM NAbs may modulate disease activity in some patients with autoimmune disease. In mechanistic studies, anti-AC NAbs were shown to act in dendritic cells by inhibition of the mitogen-activated protein kinase (MAPK) pathway, a primary signal transduction pathway that controls inflammatory responses. This immunomodulatory pathway has an absolute requirement for the induction of MAPK phosphatase-1. Taken together, recent studies have elucidated the novel properties of a class of protective NAbs, which may directly blunt inflammatory responses through a primitive pathway for regulation of the innate immune system.
immunoregulation; innate-like; natural antibody
As highlighted by the development of intestinal autoinflammatory disorders when tolerance is lost, homeostatic interactions between gut microbiota, resident immune cells, and the gut epithelium are key in the maintenance of gastrointestinal health. Gut immune responses, whether stimulatory or regulatory, are dictated by the activated dendritic cells (DCs) that first interact with microorganisms and their gene products to then elicit T and B cell responses. Previously, we have demonstrated that treatment with genetically modified Lactobacillus acidophilus is sufficient to tilt the immune balance from proinflammatory to regulatory in experimental models of colitis and colon cancer. Given the significant role of DCs in efficiently orchestrating intestinal immune responses, characterization of the signals induced within these cells by the surface layer molecules, such as lipoteichoic acid (LTA), and proteins of L. acidophilus is critical for future treatment and prevention of gastrointestinal diseases. Here, we discuss the potential regulatory pathways involved in the downregulation of pathogenic inflammation in the gut, and explore questions regarding the immune responses to LTA-deficient L. acidophilus that require future studies.
Lactobacillus acidophilus; lipoteichoic acid; S-layer proteins; gut inflammation; dendritic cells; immune regulation
The antileukemic potential of natural killer (NK) cells has been of rising interest in recent years. Interactions between inhibitory killer cell immunoglobulin-like receptors (KIR) and HLA class I ligands seem to be critically involved in the immunosurveillance process. It is also well established that mismatching of HLA class I-encoded KIR ligands in the setting of hematopoietic stem cell transplantation leads to allorecognition of leukemic cells by NK cells, which is in line with the concept of missing-self recognition. Recent data now suggest that KIR gene polymorphism constitutes another important parameter that needs to be taken into account for selection of suitable stem cell donors. Moreover, the role of KIR gene polymorphism for predisposition to leukemia is a current matter of debate. Here, we would like to review the role of KIR function and genetic polymorphism for recognition of leukemia and discuss the impact of these findings for developing novel concepts for NK cell-based immunotherapy strategies.
NK cells; KIR; leukemia; ALL; AML; oncology; HSCT
Typhoid fever, caused by S. Typhi, is responsible for approximately 200,000 deaths per year worldwide. Little information is available regarding epithelium-bacterial interactions in S. Typhi infection. We have evaluated in vitro the effects of wild-type S. Typhi, the licensed Ty21a typhoid vaccine and the leading strains CVD 908-htrA and CVD 909 vaccine candidates on intestinal barrier function and immune response. Caco2 monolayers infected with wild-type S. Typhi exhibited alterations in the organization of tight junctions, increased paracellular permeability, and a rapid decrease in Trans-Epithelial Electrical Resistance as early as 4 h post-exposure. S. Typhi triggered the secretion of interleukin (IL)-8 and IL-6. Caco2 cells infected with the attenuated strains exhibited a milder pro-inflammatory response with minimal disruption of the barrier integrity. We conclude that wild-type S. Typhi causes marked transient alterations of the intestinal mucosa that are more pronounced than those observed with Ty21a or new generation attenuated typhoid vaccine candidates.
intestinal mucosal barrier; epithelial permeability; mucosal immunity; Salmonella Typhi; typhoid vaccines; cytokines