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Results for “Adaptive Immunity”

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At least 343 records · Page 19Linked to original sources

PubMed2003

Perforin is required for innate and adaptive immunity induced by heat shock protein gp96.

Tumor-secreted gp96-Ig is highly immunogenic and triggers CD8 T cell-mediated tumor rejection. In vivo secreted gp96-Ig and gp96-myc cause NK activation and clonal expansion of specific CD8(+) CTL in wild-type and in Fas-ligand-deficient (gld) mice but not in perforin- (PKO) or IFN-gamma-deficient (GKO) mice. Transfer of perforin-competent NK cells restores the ability of PKO mice to clonally expand CD8 CTL in response to gp96-Ig. The data demonstrate an essential role for perforin-mediated functions in the activation of innate and adaptive immunity by heat shock protein gp96-peptide complexes. Crosspresentation of antigens by heat shock proteins seems to require a perforin-dependent positive feedback loop between NK and DC for both sustained NK activation and clonal CTL expansion. The studies also explain how depressed NK activity in patients with tumors or after viral infections could diminish CTL responses.

Adoptive Transfer↗

PubMed1999

Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.

Defensins contribute to host defense by disrupting the cytoplasmic membrane of microorganisms. This report shows that human beta-defensins are also chemotactic for immature dendritic cells and memory T cells. Human beta-defensin was selectively chemotactic for cells stably transfected to express human CCR6, a chemokine receptor preferentially expressed by immature dendritic cells and memory T cells. The beta-defensin-induced chemotaxis was sensitive to pertussis toxin and inhibited by antibodies to CCR6. The binding of iodinated LARC, the chemokine ligand for CCR6, to CCR6-transfected cells was competitively displaced by beta-defensin. Thus, beta-defensins may promote adaptive immune responses by recruiting dendritic and T cells to the site of microbial invasion through interaction with CCR6.

Antibodies↗

PubMed2004

The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo.

In vitro studies have indicated the importance of Toll-like receptor (TLR) signaling in response to the fungal pathogens Candida albicans and Aspergillus fumigatus. However, the functional consequences of the complex interplay between fungal morphogenesis and TLR signaling in vivo remain largely undefined. In this study we evaluate the impact of the IL-1R/TLR/myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway on the innate and adaptive Th immunities to C. albicans and A. fumigatus in vivo. It was found that 1) the MyD88-dependent pathway is required for resistance to both fungi; 2) the involvement of the MyD88 adapter may occur through signaling by distinct members of the IL-1R/TLR superfamily, including IL-1R, TLR2, TLR4, and TLR9, with the proportional role of the individual receptors varying depending on fungal species, fungal morphotypes, and route of infection; 3) individual TLRs and IL-1R activate specialized antifungal effector functions on neutrophils, which correlates with susceptibility to infection; and 4) MyD88-dependent signaling on dendritic cells is crucial for priming antifungal Th1 responses. Thus, the finding that the innate and adaptive immunities to C. albicans and A. fumigatus require the coordinated action of distinct members of the IL-1R/TLR superfamily acting through MyD88 makes TLR manipulation amenable to the induction of host resistance to fungi.

Adaptor Proteins, Signal Transducing↗

PubMed2003

IL-21 and IL-21 receptor: a new cytokine pathway modulates innate and adaptive immunity.

Interleukin (IL)-21 is a new member of the type I cytokine superfamily. Although it is most homologous to IL-15, it has a unique receptor chain, IL-21R, that pairs with the gamma-common cytokine receptor chain. The first experiments examining the biology of the IL-21 pathway reveal that it is a cytokine with effects on natural killer (NK) cells, T cells, and B cells. Mice deficient in the IL-21R have also been made, and are being examined for the effects of the IL-21/IL-21R pathway in vivo. Here we summarize our current knowledge of this new cytokine pathway, and its role in innate and adaptive immunity.

Animals↗

PubMed1994

Interleukin-12: a bridge between innate resistance and adaptive immunity with a role in infection and acquired immunodeficiency.

Interleukin-12 (IL-12) is a disulfide-linked heterodimeric cytokine originally identified as a product of EBV-transformed B cell lines. Monocyte/macrophages are the physiologically most relevant producers of IL-12, in response to both Gram-positive and -negative bacteria, bacterial products, and intracellular parasites. Although IL-12 has an enhancing effect on the survival and growth of early hematopoietic progenitor cells, most of the IL-12 biological activity has been described on T and NK cells, on which it induces production of lymphokines, primarily IFN-gamma, enhances cytotoxic activity, and, in cooperation with other stimuli, increases proliferation. IL-12 is an inducer of development of T helper type 1 (Th-1) cells and the equilibrium between IL-12 and IL-4 is probably important for the balance in vivo between Th-1 and Th-2 responses. IL-12 has an important role in the host resistance to infection, in particular to intracellular pathogens, by activating macrophages through induction of IFN-gamma from NK and T cells and by enhancing cell-mediated immune responses, dependent on Th-1 cell development. Peripheral blood mononuclear cells from HIV-seropositive individuals are impaired in their ability to produce IL-12 in response to bacterial stimulation, and IL-12 restores in vitro some of the depressed immunological functions, suggesting that a defect in IL-12 production may have a pathogenic role in the immunodeficiency of HIV-infected individuals. Natural IL-12 appears to provide a regulatory link between innate resistance and the development of the antigen-specific adaptive immune response and the recombinant protein has therapeutic potential because of its activity against tumors and infections and its effectiveness as an adjuvant enhancing cell-mediated immunity in vaccination.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Heat shock proteins and scavenger receptors: role in adaptive immune responses.

Tumor-derived heat shock proteins have shown promise as anti-cancer vaccines in clinical trials. Heat shock proteins (HSPs) can generate potent anti-tumor immunity and elicit antigen-specific CD8+ T cell responses in murine studies. Antigen presenting cells (APC), such as macrophages and dendritic cells (DCs), can elicit antigen-specific CD8+ T cell responses mediated by HSPs. CD91 was the first identified endocytic scavenger receptor for HSPs on APC that can facilitate the process of cross-presentation. Other scavenger receptors may also play a similar role in this process. The present review critically evaluates the identified HSP endocytic receptors on APCs that may generate adaptive immune responses. A better understanding of this interaction between HSPs and APCs may further unravel mechanisms of immunoadjuvant function of HSPs.

Animals↗

PubMed2005

Adaptive immune responses are dispensable for isolated lymphoid follicle formation: antigen-naive, lymphotoxin-sufficient B lymphocytes drive the formation of mature isolated lymphoid follicles.

Isolated lymphoid follicles (ILFs) are recently appreciated members of the mucosal immune system. The architecture, composition, and inducible nature of these structures indicates that these structures are tertiary lymphoid structures. The process leading to the formation of tertiary lymphoid structures, lymphoid neogenesis, has been observed in a number of inflammatory and autoimmune conditions. Given this association, there is considerable interest in identifying the factors promoting lymphoid neogenesis, and understanding the steps in this process. Using murine ILF formation as a model, we have examined the roles of different cellular sources of lymphotoxin (LT) and the adaptive immune response in lymphoid neogenesis. In this study, we report that, although other cellular sources of LT may supplant B lymphocytes in the formation of immature ILFs (loosely organized clusters of B lymphocytes), LT-sufficient B lymphocytes are required for the progression of immature ILFs to mature ILFs (organized lymphoid aggregates with a follicle-associated epithelium). ILF formation occurs in the absence of T lymphocytes and Ag-specific B lymphocyte responses, and ILF B lymphocytes express elevated levels of LT in the absence of antigenic stimulation. Consistent with a role for chemokines inducing LT expression in Ag-naive B lymphocytes, and a chemokine-driven positive-feedback loop driving mature ILF formation, mature ILFs express elevated levels of B lymphocyte chemoattractant in the absence of Ag-specific B lymphocyte stimulation. These observations indicate that ILFs contain Ag-naive lymphocytes, and suggest that events occurring within ILFs shape subsequent immune responses mediated by these lymphocytes.

Animals↗

PubMed2002

NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions.

Transcription factors of the Rel/NF-kappaB family are activated in response to signals that lead to cell growth, differentiation, and apoptosis, and these proteins are critical elements involved in the regulation of immune responses. The conservation of this family of transcription factors in many phyla and their association with antimicrobial responses indicate their central role in the regulation of innate immunity. This is illustrated by the association of homologues of NF-kappaB, and their regulatory proteins, with resistance to infection in insects and plants (M. S. Dushay, B. Asling, and D. Hultmark, Proc. Natl. Acad. Sci. USA 93:10343-10347, 1996; D. Hultmark, Trends Genet. 9:178-183, 1993; J. Ryals et al., Plant Cell 9:425-439, 1997). The aim of this review is to provide a background on the biology of NF-kappaB and to highlight areas of the innate and adaptive immune response in which these transcription factors have a key regulatory function and to review what is currently known about their roles in resistance to infection, the host-pathogen interaction, and development of human disease.

Animals↗

PubMed2002

The role of chemokines in linking innate and adaptive immunity.

It is becoming clear that chemokine function is necessary to translate an innate-immune response into an acquired response. Dendritic cells activated by innate stimuli and loaded with foreign antigen travel to regional lymph nodes to activate the acquired-immune system. Subsequently, the activated acquired-immune cells move into tissue, where the innate immune system sets-off the danger signal. The chemokine system has emerged as an essential regulator of this dendritic cell and lymphocyte trafficking, which is necessary to turn an innate immune response into an adaptive response.

Animals↗

PubMed2005

Anthrax lethal toxin-mediated killing of human and murine dendritic cells impairs the adaptive immune response.

Many pathogens have acquired strategies to combat the immune response. Bacillus anthracis interferes with host defenses by releasing anthrax lethal toxin (LT), which inactivates mitogen-activated protein kinase pathways, rendering dendritic cells (DCs) and T lymphocytes nonresponsive to immune stimulation. However, these cell types are considered resistant to killing by LT. Here we show that LT kills primary human DCs in vitro, and murine DCs in vitro and in vivo. Kinetics of LT-mediated killing of murine DCs, as well as cell death pathways induced, were dependent upon genetic background: LT triggered rapid necrosis in BALB/c-derived DCs, and slow apoptosis in C57BL/6-derived DCs. This is consistent with rapid and slow killing of LT-injected BALB/c and C57BL/6 mice, respectively. We present evidence that anthrax LT impairs adaptive immunity by specifically targeting DCs. This may represent an immune-evasion strategy of the bacterium, and contribute to anthrax disease progression. We also established that genetic background determines whether apoptosis or necrosis is induced by LT. Finally, killing of C57BL/6-derived DCs by LT mirrors that of human DCs, suggesting that C57BL/6 DCs represent a better model system for human anthrax than the prototypical BALB/c macrophages.

Journal Article↗

PubMed2003

Suppressors of cytokine signaling proteins in innate and adaptive immune responses.

Suppressors of cytokine signaling (SOCS) proteins have been identified as important mediators of negative regulatory circuits within cytokine receptor signaling. They are induced upon stimulation by an increasing set of cytokines as well as further immunological stimuli and are capable to inhibit Janus kinases and signal transducer and activator of transcription signaling. Inhibition is mediated by interfering directly with signal transduction at the receptor as well as targeting of associated molecules for proteosomal degradation. Targeted gene deletion approaches have revealed the importance of SOCS mediated termination of cytokine signaling during normal cellular activation. In addition to their function as classical feedback inhibitors SOCS proteins display a broad panel of inhibitory activity thereby mediating cross-talk modulation between different stimuli. The consequences for regulation of innate and adaptive immune responses are thus obvious. Finally, there are emerging data showing involvement of SOCS proteins in various immune diseases. Modulating SOCS activity could be a promising new approach for molecular therapeutic strategies.

Animals↗

PubMed2006

Mast cells in allergy and autoimmunity: implications for adaptive immunity.

As in the fashion industry, trends in a particular area of scientific investigation often are fleeting but then return with renewed and enthusiastic interest. Studies of mast cell biology are good examples of this. Although dogma once relegated mast cells almost exclusively to roles in pathological inflammation associated with allergic disease, these cells are emerging as important players in a number of other physiological processes. Consequently, they are quickly becoming the newest "trendy" cell, both within and outside the field of immunology. As sources of a large array of pro- and anti-inflammatory mediators, mast cells also express cell surface molecules with defined functions in lymphocyte activation and trafficking. Here, we provide an overview of the traditional and newly appreciated contributions of mast cells to both innate and adaptive immune responses.

Animals↗

PubMed2004

The anaphylatoxins bridge innate and adaptive immune responses in allergic asthma.

The complement system has long been recognized for its role as a lytic effector system that protects against microbial pathogens, as well as for its role in mediating acute and chronic inflammatory responses. Many of the inflammatory sequelae of complement activation can be related to the complement cleavage fragments C3a and C5a, the so-called anaphylatoxins (ATs). Cloning and subsequent gene targeting of their corresponding receptors, as well as generation of specific C3a and C5a inhibitors, have fueled new interest in studies aimed at defining the roles of the anaphylatoxins in inflammatory diseases. Traditionally, the anaphylatoxins have been considered mediators of end-stage effector mechanisms. However, recent data from animal models of allergic asthma suggest that C3a and C5a provide a critical link between innate and adaptive immunity. This review is aimed at outlining our current knowledge of when and where anaphylatoxins contribute to and control the development of allergic asthma. The accumulated data suggest a model in which C3a and C5a play important but opposing roles during allergen-induced T-cell polarization: C3a promotes Th2 responses, whereas C5a prevents Th2 polarization. During the effector phase, both anaphylatoxins trigger the inflammatory response and contribute to bronchoconstriction.

Allergens↗

PubMed2004

The T cell cometh: interplay between adaptive immunity and cytokine networks in rheumatoid arthritis.

The etiology of autoimmunity in humans remains poorly defined, and animal models provide a unique opportunity to study potential autoimmune mechanisms. A novel model of autoimmune inflammatory arthritis results from a point mutation in the zeta-associated-protein of 70 kDa (ZAP-70), which causes abnormal thymic T cell selection and survival of autoreactive clones. Although the resulting clinical and pathologic abnormalities are clearly T cell-dependent, macrophage and fibroblast cytokines such as IL-1 and TNF-alpha are required for full expression of the disease. The studies of Hata et al. raise the intriguing possibility that traditional proinflammatory cytokine networks represent common effector mechanisms in inflammatory joint diseases such as rheumatoid arthritis. Hence, effective therapeutic interventions can target either unique etiologic pathways related to adaptive immune responses or shared terminal mechanisms.

Animals↗

PubMed1997

New insights into the genomic organization and origin of the major histocompatibility complex: role of chromosomal (genome) duplication in the emergence of the adaptive immune system.

Recently, it became clear that the human and mouse genomes contain at least three regions paralogous to the major histocompatibility complex (MHC) region. This observation led us to the proposal that the MHC region emerged as a result of chromosomal duplication that took place at an early stage of vertebrate evolution. Here I briefly review this proposal. Accumulating evidence indicates that (a) genome-wide duplication(s) took place close to the origins of vertebrates. Taking this and others into account, I suggest that the duplication(s) involving the MHC region probably took place as a part of the genome-wide duplication(s). The human T cell receptor (TCR) and immunoglobulin (Ig) genes also appear to be located on paralogous chromosomal segments. These findings raise the possibility that the genome-wide duplication provided a major impetus not only to the emergence of the full-fledged MHC system, but also to the appearance of other key molecules of the adaptive immune system such as TCR and Ig.

Animals↗

PubMed2002

Effects of IL-12 and IL-23 on antigen-presenting cells at the interface between innate and adaptive immunity.

Recent evidence from different experimental systems has demonstrated that autocrine activation of antigen-presenting cells (APCs) may be important at the initiation of an immune response, and that a specific set of cytokines may meet the dual needs of activating APCs and priming and/or maintaining the antigen-specific T-cell response. Composite factors with p40, including IL-12 (p40/p35) and IL-23 (p40/p19), may be two such immunoregulatory cytokines, their effects encompassing actions on both myeloid APCs and T cells. However, although both cytokines enhance the Th1 costimulatory functions of APCs, and IL-23 does induce IL-12 from APCs, their effects, which in part overlap, can be differentiated from one another. This review summarizes recent data on the actions of IL-12 and IL-23 on dendritic cells and macrophages at the interface between innate and adaptive immunity.

Animals↗

PubMed2003

Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems.

Secretory IgA (SIgA) is a multi-polypeptide complex consisting of a secretory component (SC) covalently attached to dimeric IgA containing one joining (J) chain. We present the analysis of both the N- and O-glycans on the individual peptides from this complex. Based on these data, we have constructed a molecular model of SIgA1 with all its glycans, in which the Fab arms form a T shape and the SC is wrapped around the heavy chains. The O-glycan regions on the heavy (H) chains and the SC N-glycans have adhesin-binding glycan epitopes including galactose-linked beta1-4 and beta1-3 to GlcNAc, fucose-linked alpha1-3 and alpha1-4 to GlcNAc and alpha1-2 to galactose, and alpha2-3 and alpha2-6-linked sialic acids. These glycan epitopes provide SIgA with further bacteria-binding sites in addition to the four Fab-binding sites, thus enabling SIgA to participate in both innate and adaptive immunity. We also show that the N-glycans on the H chains of both SIgA1 and SIgA2 present terminal GlcNAc and mannose residues that are normally masked by SC, but that can be unmasked and recognized by mannose-binding lectin, by disrupting the SC-H chain noncovalent interactions.

Chromatography, High Pressure Liquid↗

PubMed2003

Cutting edge: link between innate and adaptive immunity: Toll-like receptor 2 internalizes antigen for presentation to CD4+ T cells and could be an efficient vaccine target.

An ideal vaccine for induction of CD4(+) T cell responses should induce local inflammation, maturation of APC, and peptide loading of MHC class II molecules. Ligation of Toll-like receptor (TLR) 2 provides the first two of these three criteria. We have studied whether targeting of TLR2 results in loading of MHC class II molecules and enhancement of CD4(+) T cell responses. To dissociate MHC class II presentation from APC maturation, we have used an antagonistic, mouse anti-human TLR2 mAb (TL2.1) as ligand and measured proliferation of a mouse Ckappa-specific human CD4(+) T cell clone. TL2.1 mAb was 100-1000 times more efficiently presented by APC compared with isotype-matched control mAb. Moreover, TL2.1 mAb was internalized into endosomes and processed by the conventional MHC class II pathway. This novel function of TLR2 represents a link between innate and adaptive immunity and indicates that TLR2 could be a promising target for vaccines.

Amino Acid Sequence↗