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Results for “Adaptive Immunity”

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At least 1,387 records · Page 77Linked to original sources

PubMed2003

A survival game of hide and seek: cytomegaloviruses and MHC class I antigen presentation pathways.

Cytomegaloviruses (CMV) are members of the ubiquitous family of herpesviruses, which escape immunological clearance and persist throughout life in the infected host. Cytomegaloviruses have developed numerous strategies that permit them to co-exist with their host even as an anti-virus immune response endangers their long-term survival. A considerable number of these strategies are aimed at MHC class I presentation of viral proteins to CD8+ T cells (TCD8+ ). Although the gamut of CMV immune evasion will be briefly examined, the primary focus of this review is on the host ability to counteract the strategies developed by CMV to inhibit antigen processing and presentation. A primary mechanism used by the immune system is the recognition of very early virus proteins including recognition of the immunomodulatory proteins themselves. We further speculate that cross-presentation of antigen is an adaptive immune response to the inhibition of direct presentation. Other mechanisms, such as the evolution of pAPC subsets, may also allow the immune system to adapt to a variety of different infectious pathogens while preventing cytopathic infection of all pAPCs.

Animals↗

PubMed2026

Programmed cell death-1: from a T-cell immune checkpoint to a regulator of Natural Killer cell biology.

Programmed cell death protein 1 (PD-1, CD279) is a pivotal inhibitory immune checkpoint receptor that plays a central role in maintaining immune homeostasis and peripheral tolerance. Originally characterized as a negative regulator of T-cell activation, PD-1 limits excessive immune responses and prevents autoimmunity, while its sustained expression under conditions of chronic antigen stimulation contributes to T-cell dysfunction and exhaustion. The discovery that blockade of the PD-1 pathway can restore anti-tumor immunity has revolutionized cancer therapy and established immune checkpoint inhibition as a cornerstone of modern oncology. Although PD-1 has traditionally been viewed as a key regulator of adaptive immunity, accumulating evidence indicates that its biological functions extend beyond T cells. In recent years, PD-1 expression has been identified in several innate immune cell populations, particularly Natural Killer (NK) cells, where it has emerged as an important modulator of effector functions, cytokine production, metabolic fitness, and antitumor activity. These findings have challenged the classical view of PD-1 biology and revealed unexpected similarities between NK-cell dysfunction and the exhausted phenotype described in chronically stimulated T cells. In the tumor microenvironment, PD-1 expression on NK cells has been associated with impaired cytotoxicity and reduced immune surveillance, suggesting that NK cells may also represent relevant targets of PD-1-mediated immunosuppression. At the same time, the mechanisms regulating PD-1 expression and signaling in NK cells appear to differ, at least in part, from those operating in T lymphocytes, highlighting the complexity of this pathway across distinct immune cell subsets. In this review, we summarize the current knowledge of PD-1 biology, from its established role in T-cell regulation to its emerging functions in NK cells. We discuss the molecular mechanisms governing PD-1 expression and signaling, its contribution to immune dysfunction in cancer and chronic diseases, and the potential implications of targeting the PD-1 axis to enhance both adaptive and innate antitumor immunity.

Natural Killer (NK) cells↗

PubMed2005

An essential role for Rxr alpha in the development of Th2 responses.

A viable hypomorphic allele of mouse retinoid X receptor alpha (Rxralpha) was created by random germline mutagenesis. The mutation (I273N) alters the ligand binding and heterodimerization domain, and causes a 90% decline in ligand-inducible transactivation. Homozygotes develop progressive alopecia and dermal cysts, and progressive exaggeration of Th1 and loss of Th2 responses to antigen. Th1 skewing is directly caused by aberrant function of both antigen-presenting cells and naïve CD4 T cells; the predominant Th1 response to antigen is attributable to decreased suppression of regulatory T cells in mutant mouse. Dietary depletion of vitamin A in Th2-prone wild-type mice mimics the immune phenotype caused by the mutation. Hence, RXRalpha plays an important post-developmental role in the regulation of adaptive immune responses, and provides a plausible link between nutritional environment and the type of adaptive response that results from immunization.

Aging↗

PubMed1994

Modern concepts in immune recognition and lymphocyte activation. Relevance for the development of useful vaccines.

Adaptive immunity requires both specific recognition of an antigen and its translation into appropriate lymphocyte responses. This paper reviews the striking differences in B- and T-lymphocyte antigen recognition, details the pathways for conversion of protein antigens into peptide-major histocompatibility complex molecule ligands for T-cell receptors, and summarizes the roles of costimulatory signals in lymphocyte activation. This information is used to suggest new approaches for the rational design of vaccines.

Antigen Presentation↗

PubMed2006

Dendritic cells: not just another cell type in the kidney, but a complex immune sentinel network.

Dendritic cells (DCs) are crucial for inducing and regulating adaptive immunity. These cells also exist in the kidney, where, however, their function had been unknown. A study by Soos et al. now demonstrates that renal DCs form an intricate cellular network that continuously surveys the tubulointerstitium, and reveals a previously unrecognized immune sentinel system of the kidney.

Animals↗

PubMed2004

Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger.

Stimulation of certain cytokine and pattern recognition receptors enhances adaptive immune responses, and in chronic situations, may play a role in the loss of self-tolerance. We hypothesized that in addition to upregulating positive immune receptors (i.e. co-stimulatory molecules), certain cytokine and pattern recognition signals might downregulate negative immune receptors, removing a potential barrier to lymphocyte responsiveness. The newly identified CD28 family member Programmed Death-1 (PD-1) is an inhibitory receptor involved in peripheral tolerance, as evidenced by the frank autoimmunity and autoantibody formation found in PD-1-deficient mice. Here we report that antigen-receptor induced PD-1 expression on murine B cells is markedly reduced by certain signals associated with immune system danger, including LPS, CpG oligodeoxynucleotides and several pro-inflammatory cytokines, through distinct signaling pathways. We further report for the first time that engagement of PD-1 inhibits cell cycle progression in primary B cells and that modulation of PD-1 expression by CpG or IL-4 significantly reverses such inhibition. Our data suggest a novel mechanism for enhancement of normal immune responses and disruption of normal tolerance mechanisms.

Animals↗

PubMed2004

Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion.

DCs play a pivotal role in bringing forth innate and adaptive immune responses. Viruses can specifically target DCs, rendering them ineffective in stimulating T cells, which can ultimately lead to immunosuppression. In the present study we have identified several potential mechanisms by which lymphocytic choriomeningitis virus (LCMV) induces immunosuppression in its natural murine host. The immunosuppressive LCMV variant clone 13 (Cl 13) infects DCs and interferes with their maturation and antigen-presenting capacity as evidenced by a significant reduction in the surface expression of MHC class I, MHC class II, CD40, CD80, and CD86 molecules. Additionally, Cl 13 infects hematopoietic progenitor cells both in vivo and in vitro, impairing their development. One mechanism by which hematopoietic progenitors are developmentally impaired is through the Cl 13-induced production of IFN-alpha and IFN-beta (IFN-alpha/beta). Mice deficient in the receptor for IFN-alpha/beta show a normal differentiation of progenitors into DCs despite viral infection. Thus, a virus can evolve a strategy to boost its survival by preventing the maturation of DCs from infected progenitor cells and by reducing the expression of antigen-presenting and costimulatory molecules on developed DCs.

Animals↗

PubMed2006

Dendritic cells and HIV infection: activating dendritic cells to boost immunity.

Dendritic cells (DCs) are white blood cells that coordinate innate and adaptive immunity. They are distributed within epithelia and mucosal-associated lymphoid tissues, positioned to entrap incoming pathogens or vaccines. Human immunodeficiency virus (HIV) and the non-human primate equivalent (SIV) exploit DCs to amplify infection, underscoring the need to harness strategies that promote presentation of virus by DCs to stimulate potent anti-viral immunity instead of virus transmission. Two main subsets of DCs need to be considered: myeloid (MDC) and plasmacytoid (PDC) subsets. Using the SIV-macaque system to advance oral vaccine research, we examined macaque PDC and MDC biology, identifying ways to activate DCs and boost antiviral immunity. Immunostimulatory oligodeoxyribonucleotides (ISS-ODNs) stimulated PDC/MDC mixtures to up-regulate co-stimulatory molecule expression and to secrete both IFN-alpha and IL-12. Additionally, ISS-ODNs augmented SIV-specific IFN-gamma responses induced by virus-bearing DCs. ISS-ODN-driven DC activation is being pursued to improve oral/nasopharyngeal mucosal vaccines and therapies against HIV.

AIDS Vaccines↗

PubMed2004

TGF-beta: the perpetrator of immune suppression by regulatory T cells and suicidal T cells.

Innate and adaptive immunity function to eliminate foreign invaders and respond to injury while enabling coexistence with commensal microbes and tolerance against self and innocuous agents. Although most often effective in accomplishing these objectives, immunologic processes are not fail-safe and may underserve or be excessive in protecting the host. Checks and balances to maintain control of the immune system are in place and are becoming increasingly appreciated as targets for manipulating immunopathologic responses. One of the most recognized mediators of immune regulation is the cytokine transforming growth factor-beta (TGF-beta), a product of immune and nonimmune cells. Emerging data have unveiled a pivotal role for TGF-beta as a perpetrator of suppression by CD4(+)CD25(+) regulatory T (Treg) cells and in apoptotic sequelae. Through its immunosuppressive prowess, TGF-beta effectively orchestrates resolution of inflammation and control of autoaggressive immune reactions by managing T cell anergy, defining unique populations of Treg cells, regulating T cell death, and influencing the host response to infections.

Animals↗

PubMed2006

Autophagy in immune defense against Mycobacterium tuberculosis.

Autophagy is a newly recognized innate and adaptive immunity defense against intracellular pathogens, in keeping with its role as a cytoplasmic maintenance pathway. Induction of autophagy by physiological, pharmacological or immunological means can eliminate intracellular Mycobacterium tuberculosis, providing one of the first examples of the immunological role of autophagy. Under normal circumstances, M. Tuberculosis survives in macrophages by inhibiting phagolysosome biogenesis. Induction of autophagy overcomes the mycobacterial phagosome maturation block, and delivers the tubercle bacilli to degradative compartments where they are eliminated.

Autophagy↗

PubMed2005

Heat shock proteins HSP70 and GP96: structural insights.

Several heat shock proteins (HSPs) act as potent adjuvants for eliciting anti-tumor immunity. HSP-based tumor vaccine strategies have been highly successful in animal models and are undergoing testing in clinical trials. It is generally accepted that HSPs, functioning as chaperones for tumor antigens, elicit tumor-specific adaptive immune responses. HSPs also appear to induce innate immune responses in an antigen-independent fashion. Innate responses generated by HSPs may contribute to anti-tumor immunity. Immunologically active chaperones with anti-tumor activity are referred to as "immunochaperones". Here, we review the studies that address the role of structural domains or regions of the immunochaperones HSP70 and GP96 that may be involved in the induction of adaptive or innate immune responses.

Animals↗

PubMed2002

T cell-dependent and -independent pathways to tissue destruction following herpes simplex virus-1 infection.

Viral infections can trigger tissue destruction through innate and/or adaptive immune mechanisms. Here we show that these pathways can be differentially activated after infection by different strains of the herpes simplex virus-1 (HSV-1) virus. Infection of murine corneal tissue by HSV-1 (KOS) triggers an autoreactive clone of CD4 cells that is cross-reactive with an HSV-1 epitope to initiate corneal destruction. In contrast, ocular infection by the HSV-1 (RE) strain induces murine corneal destruction through direct, T cell-independent, activation of the innate immune system. Although the relative role of these two pathways to blindness following clinical HSV-1 ocular infection is unknown, this analysis suggests a general experimental approach to evaluate the relative contribution of adaptive and innate immune mechanisms to virally induced host tissue destruction.

Animals↗

PubMed1998

Neuroimmunoregulation and natural immunity.

The development and function of the immune system is regulated by neuroendocrine factors. Immune function may be divided into adaptive and natural immunity. Adaptive immune responses are driven by specific determinants of the antigen (epitopes), require 5-10 d to fully develop, and show an accelerated or memory response after repeated exposure to the same antigen. Natural immunity may be divided into host defense mediated by non-immune factors (e.g., antimicrobial proteins, enzymes, mucus etc.) and polyspecific responses of the immune system. This polyspecific response relies on natural antibodies and on some other serum proteins (e.g., lipopolysaccharide-binding protein-LBP, C-reactive protein-CRP), and on surface receptors of macrophages, natural killer cells and B and T lymphocytes for activation. Highly conserved homologous (crossreactive) epitopes, or homotopes for short, are recognized by the natural immune system. Natural antibodies, LBP, and CRP are capable of activating the entire immune system after combination with the appropriate homotope. During febrile illness natural immune host defense is promptly elevated because of the rapid rise of natural antibodies, LBP, and CRP in the serum. This is known as the acute phase response (APR), which is initiated by a sudden rise of cytokines in the circulation, such as IL-1, IL-6, and TNF-alpha. The cytokines act on the brain, the neuroendocrine system, and on other tissues and organs, which leads to fever and profound hormonal and metabolic changes. The hypothalamus-pituitary adrenal axis is activated and serves as the primary regulator of immune and inflammatory reactions. Insulin, glucagon, and catecholeamine levels are also raised. Bone marrow activity and leukocyte function are high and the liver is converted to the rapid production of acute-phase proteins (APP). APP include LBP, CRP, fibrinogen, some complement components, enzyme inhibitors, and anti-inflammatory proteins, which may rise in the serum from several hundred to a thousand times within 24-48 hr. Therefore, natural immunity is a polyspecific response to homotopes, which functions as an instantaneous defense mechanism in health and which is rapidly boosted by cytokines and hormones during febrile illness. This is a highly successful defense reaction, as in the overwhelming majority of cases, febrile illness leads to recovery and the development of adaptive immunity in man and higher animals.

Acute-Phase Reaction↗

PubMed2004

Common variable immunodeficiency is associated with defective functions of dendritic cells.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and defects in T-cell functions that could be primary or secondary. We addressed whether CVID is associated with impairment in the dendritic cell (DC) compartment, as DCs play a central role in the development of adaptive immunity. We demonstrate that DCs from CVID patients display severely perturbed differentiation, maturation, and function, and express markedly reduced levels of the costimulatory molecules that are critical for T-cell stimulation. Patients' DCs induced weak proliferation of allogeneic T cells and produced significantly low amounts of interleukin-12 (IL-12) upon CD40 signaling. Multiple defects in the immune system, including malfunctioning of DCs, appear to be prominent features of CVID patients. Impairment in both the innate and adaptive compartments of the immune system may thus cumulatively account for the inability of CVID patients to eradicate pathogens through conventional immune pathways, thus resulting in an increased risk for recurrent bacterial infections.

Cell Differentiation↗

PubMed2003

Molecular basis of the inflammatory response to adenovirus vectors.

Adenovirus vectors are extensively studied in experimental and clinical models as agents for gene therapy. Recent generations of helper-dependent adenovirus vectors have the majority of viral genes removed and result in vectors with a large carrying capacity, reduced host adaptive immune responses and improved gene transfer efficiency. Adenovirus vectors, however, activate innate immune responses shortly after administration in vivo. Unlike the adaptive response, the innate response to adenovirus vectors is transcription independent and is caused by the viral particle or capsid. This response results in inflammation of transduced tissues and substantial loss of vector genomes in the first 24 h. The adenovirus capsid activates a number of signaling pathways following cell entry including p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) that ultimately lead to expression of proinflammatory genes. Various cytokines, chemokines and leukocyte adhesion molecules are induced by the adenovirus particle in a wide range of cell types providing a molecular basis for the inflammatory properties of these vectors. An understanding of the innate response to adenovirus vectors is essential to overcome the last remaining hurdle to improve the safety and effectiveness of these agents.

Adenoviridae↗

PubMed2005

HIV-1 and the hijacking of dendritic cells: a tug of war.

Dendritic cells are critical for host immunity and are involved both in the innate and adaptive immune responses. They are among the first cells targeted by HIV-1 in vivo at mucosal sites. Dendritic cells can sequester HIV-1 in endosomal compartments for several days and transmit infectious HIV-1 to interacting T cells in the lymph node, which is the most important site for viral replication and spread. Initially, the cellular immune response developed against HIV-1 is strong, but eventually it fails to control and resolve the infection. The most dramatic effect seen on the immune system during untreated HIV-1 infection is the destruction of helper CD4(+) T cells, which leads to subsequent immune deficiency. However, the immunomodulatory effects of HIV-1 on different dendritic cell subpopulations may also play an important role in the pathogenesis of HIV-1. This review discusses the effects HIV-1 exerts on dendritic cells in vivo and in vitro, including the binding and uptake of HIV by dendritic cells, the formation of infectious synapses, infection, and the role of dendritic cells in HIV-1 pathogenesis.

Animals↗

PubMed2005

Coeliac disease.

Coeliac disease is a gluten-sensitive enteropathy characterized by villous atrophy, hyperplastic crypts and increased numbers of intraepithelial lymphocytes which are reversed by gluten withdrawal. Diverse autoimmune disorders are frequently associated with the disease, and patients also carry an increased risk of gastrointestinal malignancy. This review is aimed at outlining the current knowledge on the contribution of the innate immunity to the whole progress of coeliac disease, catalogued as the prototype of an immune-mediated response dominated by the activation of the adaptive immune system. The accumulated data suggest a model in which the gliadin moiety triggers the upregulation of costimulatory molecules on antigen presenting cells in the lamina propria, and the generation of specialized functions on intraepithelial lymphocytes. In the lamina propria, gliadin effects are essential for the generation of a robust T cell response while in the epithelial compartment, gliadin effects confer both innate-like and TCR-mediated cytotoxicity strongly contributing to tissue injury.

Celiac Disease↗

PubMed2006

Toll-like receptor 9 contributes to recognition of Mycobacterium bovis Bacillus Calmette-Guérin by Flt3-ligand generated dendritic cells.

Recognition of mycobacteria by the innate immune system is essential for the development of an adaptive immune response. Mycobacterial antigens stimulate antigen presenting cells (APCs) through distinct Toll-like receptors (TLRs) resulting in rapid activation of the innate immune system. The role of TLRs during infection with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been evaluated for TLR2 and TLR4 only. Surprisingly, despite the fact that immune stimulatory CpG-motifs have been originally derived from BCG, for the vaccine strain the role of TLR9 has not been addressed before. To identify the set of TLRs involved in the recognition of BCG, we infected bone marrow-derived macrophages and bone marrow-derived dendritic cells (Flt3-ligand generated DCs) from TLR2, TLR3, TLR4, TLR7, TLR9, MyD88 knockout, TLR2/4 and TLR2/4/9 multiple knockout mice. The degree of activation and stimulation was determined by TNFalpha, IL-6 and IL-12p40 ELISA. Activation of DCs was measured by surface expression of the costimulatory molecule CD86. We observed the most dramatic reduction of the inflammatory response for TLR2-deficient antigen presenting cells. Both macrophages and DCs produce markedly decreased amounts of TNFalpha and IL-6 in the absence of TLR2 whereas no significant reduction could be observed for TLR3, 4, 7, 9 single TLR-knockouts. However, IL-12 production in DCs appears not exclusively dependent on TLR2 and only in TLR2/4/9-deficient DCs BCG-induced IL-12 is reduced to background levels. Similarly, up-regulation of CD86 is abolished only in TLR2/4/9-deficient DCs supporting a role of TLR9 in the recognition of M. bovis BCG by murine dendritic cells.

Animals↗