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Results for “Adaptive Immunity”

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PubMed2001

Adaptive immune responses of patients with asthma to the attachment (G) glycoprotein of respiratory synctial virus.

A history of acute bronchiolitis in infancy caused by respiratory syncytial virus is a risk factor for recurrent wheezing in early childhood. Because the attachment (G) protein sensitizes mice for pulmonary eosinophilia and because Th2 cells are central in the pathogenesis of asthma, plasma and peripheral blood mononuclear cells (PBMC) from donors with asthma and from healthy donors were evaluated for anti-G protein responses. A significant trend connecting severity of asthma with anti-G protein IgG1 and IgG2 titers was observed. The correlation between anti-F protein IgG3 titers and asthma severity approached significance. Peptide mapping studies revealed that more positive recall responses (interferon-gamma and interleukin-10 secretion) occurred after PBMC from donors with asthma were stimulated with peptides representing the nonglycosylated domain of G protein. The same peptides elicited more positive recall responses (proliferation and interferon-gamma secretion) in the PBMC of healthy donors. These data suggest that a mechanism may exist whereby adaptive immune responses against G protein contribute to wheezing.

Adolescent↗

PubMed2004

Qa-1, a nonclassical class I histocompatibility molecule with roles in innate and adaptive immunity.

Qa-1, a nonclassical class I histocompatibility molecule expressed in mice, predominantly assembles with a single nonameric peptide, Qdm, derived from the signal sequence of certain class Ia molecules. The Qa-1/Qdm complex is the primary ligand for CD94/NKG2A inhibitory receptors expressed on a major fraction of natural killer (NK) cells. Cells become susceptible to killing by NK cells under conditions where surface expression of the Qa-1/Qdm inhibitory ligand is reduced. The CD94/NKG2 "missing-self" recognition system serves as mechanism for removing cells that have abnormalities in the intracellular machinery required for assembly and expression of class I-peptides complexes, as a consequence of viral infection, for example. Despite its highly focused peptide-binding specificity, Qa-1 also has a capacity to act as an antigen-presentation molecule for CD8+ T cells. It appears that a small subpopulation of these T cells undergoes positive selection by interaction with Qa-1 in the thymus, and they maintain their specificity for Qa-1 after maturation. The role of these unusual T cells in adaptive immune responses remains to be defined.

Animals↗

PubMed2004

The role of CD94/NKG2 in innate and adaptive immunity.

CD94/NKG2 is a heterodimer expressed on natural killer (NK) and a small subset of T cells. This receptor varies in function as an inhibitor or activator depending on which isoform of NKG2 is expressed. The ligand for CD94/NKG2 is HLA-E in human and its homolog, Qa1 in mouse, which are both nonclassical class I molecules that bind leader peptides from other class I molecules. Although <5% of CD8 T cells express the receptor in a naïve mouse, its expression is upregulated upon specific recognition of antigen. Similar to NK cells, most CD8 T cells that express high levels of CD94 co-express NKG2A, the inhibitory isoform. The engagement of this receptor can lead to a blocking of cytotoxicity. However, these receptors have also been implicated in the cell survival of both NK and CD8 T cells. The level of CD94 expression is inversely correlated with the level of apoptosis in culture. Thus, CD94/NKG2 receptors may regulate effector functions and cell survival of NK cells and CD8 T cells, thereby playing a crucial role in the innate and adaptive immune response to a pathogen.

Animals↗

PubMed2000

CD1 proteins: targets of T cell recognition in innate and adaptive immunity.

The CD1 family consists of antigen presenting molecules encoded by genes located outside of the major histocompatibility complex. CD1 proteins are conserved among mammalian species and are expressed on the surface of cells involved in antigen presentation. The CD1 system has been shown to be involved in activation of cell-mediated responses, and T cells specific for either CD1 molecules or antigens presented by CD1 have been isolated. Structural and biochemical analyses demonstrate that antigens presented by CD1 are nonpeptide lipid or glycolipid structures, including examples found in the cell walls of pathogenic mycobacteria. The hydrophobic part of these antigens most likely binds in the CD1 ligand-binding groove, whereas the polar headgroup of these antigens appears to make direct contact with the T cell receptor and determines specific recognition. Presentation of antigens by CD1 molecules requires uptake and intracellular processing by antigen presenting cells and can be achieved for both exogenous and endogenous antigens. T cells recognizing CD1 restricted antigens have a broad range of functional activities that suggest that the CD1 system is involved in both innate and adaptive immune responses against microbial infections.

Animals↗

PubMed2001

Human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy maintain activated CD8+ T cell subsets as a strong adaptive immune response to cytomegalovirus.

CD8(+) T lymphocyte function specific for human cytomegalovirus (CMV) was evaluated in 14 patients infected with human immunodeficiency virus (HIV) receiving highly active antiretroviral therapy (HAART) and 26 CMV-seropositive donors without HIV infection. Fifty-seven percent of the HIV-infected group had CMV-specific cytolytic activity in freshly isolated peripheral blood mononuclear cells (PBMC) against targets expressing CMV pp65. Both interferon (IFN)-gamma secretion by CD8(+) T cells and the frequency of human leukocyte antigen (HLA)-tetramer-positive T cells in HLA-A*0201-positive HIV-infected subjects correlated with CMV-specific cytolysis. In contrast, PBMC from healthy CMV-seropositive donors did not have either measurable CMV-specific cytolysis or secretion of IFN-gamma without in vitro stimulation. The T helper response to CMV antigens was vigorous in healthy CMV-seropositive donors but low in the cohort of HIV-infected patients. Potent CD8(+) cytotoxic T lymphocyte responses to CMV in HIV-infected patients receiving HAART is the converse of what is found in healthy CMV-seropositive subjects and may be the predominant adaptive immune response against CMV in HIV-infected patients.

AIDS-Related Opportunistic Infections↗

PubMed2001

Eukaryotic heat shock proteins as molecular links in innate and adaptive immune responses: Hsp60-mediated activation of cytotoxic T cells.

Heat shock proteins (HSP) like Hsp60, Hsp70 and gp96 act directly on antigen-presenting cells (APC), e.g. by inducing the secretion of cytokines. Here we analyzed the impact of Hsp60 on the antigen-specific activation of CD8(+) T cells in a TCR transgenic system. Hsp60 induced low amounts of IFN-gamma in the absence of antigenic peptide; however, the release of IFN-gamma is increased by a factor of 3-10 following the addition of Hsp60 to purified populations of OT-1 [ovalbumin (OVA)257-264/H2-K(b)-restricted] T cells and antigen-pulsed peritoneal exudate cells (PEC) as APC. This effect is strictly correlated with the PEC ability to produce IL-12. In contrast, antigen-specific IL-2 secretion and T cell proliferation was not changed in the presence of Hsp60. Hsp60-containing OT-1 T cell cultures produced IFN-gamma even when the number of antigenic MHC class I complexes was too low to be stimulatory and could not be detected with specific mAb. Hsp60, thus, acts as a catalyzing molecule to initiate both innate and adaptive immune responses, and its presence (e.g. during an infection with cellular destruction) has direct consequences for the activation of otherwise 'ignorant' antigen-specific T cells.

Animals↗

PubMed2001

Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses.

Autocrine activation of APC by IL-12 has recently been revealed; we demonstrate here that inducible expression of Stat4 in APC is central to this process. Stat4 is induced in dendritic cells (DC) in a maturation-dependent manner and in macrophages in an activation-dependent manner. Stat4 levels directly correlate with IL-12-dependent IFN-gamma production by APC as well as IFN-gamma production by DC during Ag presentation. The Th2 cytokines IL-4 and IL-10 suppress Stat4 induction in DC and macrophages when present during maturation and activation, respectively, diminishing IFN-gamma production. In contrast, IL-4 has no effect on Stat4 levels in mature DC and actually augments IFN-gamma production by DC during Ag presentation, indicating that IL-4 acts differently in a spatiotemporal manner. The functional importance of Stat4 is evident in Stat4(-/-) DC and macrophages, which fail to produce IFN-gamma. Furthermore, Stat4(-/-) macrophages are defective in NO production in response to IL-12 and are susceptible to TOXOPLASMA: Autocrine IL-12 signaling is required for high-level IFN-gamma production by APC at critical stages in both innate and adaptive immunity, and the control of Stat4 expression is likely an important regulator of this process.

Animals↗

PubMed2006

Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity.

Immune responses are initiated when molecules of microbial origin are sensed by the Toll-like receptors (TLRs). We now report the identification of essential molecular components for the trafficking of the lipopolysaccharide (LPS) receptor complex. LPS was endocytosed by a receptor-mediated mechanism dependent on dynamin and clathrin and colocalized with TLR4 on early/sorting endosomes. TLR4 was ubiquitinated and associated with the ubiquitin-binding endosomal sorting protein hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs. Inhibition of endocytosis and endosomal sorting increased LPS signaling. Finally, the LPS receptor complex was sorted to late endosomes/lysosomes for degradation and loading of associated antigens onto HLA class II molecules for presentation to CD4+ T cells. Our results show that endosomal trafficking of the LPS receptor complex is essential for signal termination and LPS-associated antigen presentation, thus controlling both innate and adaptive immunity through TLR4.

Antigen Presentation↗

PubMed2005

IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses.

The role of NK cells following solid organ transplantation remains unclear. We examined NK cells in acute allograft rejection using a high responder model (DA-->Lewis) of rat orthotopic liver transplantation. Recipient-derived NK cells infiltrated liver allografts early after transplantation. Since chemokines are important in the trafficking of cells to areas of inflammation, we determined the intragraft expression of chemokines known to attract NK cells. CCL3 was significantly increased in allografts at 6 h post-transplant as compared to syngeneic grafts whereas CCL2 and CXCL10 were elevated in both syngeneic and allogeneic grafts. CXCL10 and CX3CL1 were significantly upregulated in allografts by day 3 post-transplant as compared to syngeneic grafts suggesting a role for these chemokines in the recruitment of effector cells to allografts. Graft-infiltrating NK cells were shown to be a major source of IFN-gamma, and IFN-gamma levels in the serum were markedly increased, specifically in allograft recipients, by day 3 post-transplant. Accordingly, in the absence of NK cells the levels of IFN-gamma were significantly decreased. Furthermore, graft survival was significantly prolonged. These data suggest that IFN-gamma-producing NK cells are an important link between the innate and adaptive immune responses early after transplantation.

Animals↗

PubMed2003

Ikaros family members from the agnathan Myxine glutinosa and the urochordate Oikopleura dioica: emergence of an essential transcription factor for adaptive immunity.

The Ikaros multigene family encodes a number of zinc finger transcription factors that play key roles in vertebrate hemopoietic stem cell differentiation and the generation of B, T, and NK cell lineages. In this study, we describe the identification and characterization of an Ikaros family-like (IFL) protein from the agnathan hagfish Myxine glutinosa and the marine urochordate Oikopleura dioica, both of which lie on the evolutionary boundary between the vertebrates and invertebrates. The IFL molecules identified in these animals displayed high conservation in the zinc finger motifs critical for DNA binding and dimerization in comparison with those of jawed vertebrates. Expression of the IFL gene in hagfish was strongest in blood, intestine, and gills. In O. dioica, transcription from the IFL gene was initiated at or around the time of hatching and maintained throughout the life span of the animal. In situ hybridization localized O. dioica IFL expression to the Fol cells, which are responsible for generating the food filter of the house. Biochemical analysis of the DNA binding and dimerization domains from M. glutinosa and O. dioici IFLs showed that M. glutinosa behaves as a true Ikaros family member. Taken together, these results indicate that the properties associated with the Ikaros family preceded the emergence of the jawed vertebrates and thus adaptive immunity.

Amino Acid Sequence↗

PubMed2002

Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia.

We previously developed a murine model of acute promyelocytic leukemia (APL) by using human cathepsin G gene regulatory elements to direct the expression of promyelocytic leukemia (PML)/retinoic acid receptor alpha (RAR alpha) and RAR alpha/PML fusion cDNAs to the early myeloid compartment of transgenic mice. To study the efficacy of noncytotoxic therapy in this animal model, cohorts of naive immunocompetent mice were inoculated with primary murine APL cells from a frozen tumor bank. Arsenic trioxide and liposomally encapsulated all-trans-retinoic acid (Lipo ATRA), alone or in combination, were administered for 21 days by i.p. injection using doses that yielded plasma levels similar to those observed in human APL patients treated with these agents. Lipo ATRA was highly effective in inducing durable molecular remissions in immunocompetent mice [C57BL/6 x C3H F(1) (B6C3HF1)]; arsenic therapy was much less effective, and did not clearly synergize with Lipo ATRA to increase the remission rate in immunocompetent mice. The survival of Lipo ATRA-treated severe combined immunodeficient (SCID) animals (lacking functional T and B cells) was inferior to that of immunocompetent B6C3HF1 recipients (40% vs. 88% survival at 1 y, P < 0.001). These data suggest that adaptive immunity cooperates with pharmacologic therapy to induce or maintain remissions in murine APL. It also implies that immunosuppressive anti-leukemia therapies could paradoxically blunt effective anti-leukemia immune responses that are important for clearing small numbers of residual tumor cells after chemotherapy-mediated cytoreduction.

Animals↗

PubMedDate not supplied

C-type lectins and galectins mediate innate and adaptive immune functions: their roles in the complement activation pathway.

In recent years, a 'new' pathway for complement activation mediated by the mannose-binding lectin (MBL) has been described as a key mechanism for the mammalian acute phase response to infection. This complement activation pathway is initiated by a non-self recognition step: the binding of a humoral C-type lectin [mannose-binding lectin (MBL)] to microbial surfaces bearing 'foreign' carbohydrate determinants. The recognition factor, MBL, is associated with a serine protease [MBL-associated serine protease (MASP)] which, upon MBL binding to the microbial ligand, activates the complement component C3, leading to either (a) phagocytosis of the opsonized target via the complement receptor, or (b) humoral cell killing via assembly of the membrane attack complex. Galectins (formerly known as S-type lectins) modulate activity of the complement receptor 3 (CR3), the macrophage membrane receptor for complement components C3b and iC3b, downstream products of the MBL pathway which are covalently bound to 'target cells. Galectins also mediate macrophage- and dendrocyte-adhesion to lymphocytes activated by signaling through another C-type lectin, the L-selectin, leading to immunoglobulin-mediated responses. Thus, the functional interplay of MBL, galectins and L-selectin in the acute phase response neutralizes the microbial challenge, and lead to further adaptive immunity. Although the observation of various components of the lectin pathway in different invertebrate species demonstrates the high conservation and ancient roots of the components of innate immunity, there has previously been no evidence supporting the possibility that the integral lectin-mediated complement activation pathway is present in invertebrates. We now have evidence for the coexistence of homologs of all the pathway's key components (MBL, MASP, C3, and galectin) in the protochordate Clavelina picta, suggesting the lectin-mediated pathway of complement activation preceded the immunoglobulin pathway in evolution. Therefore, despite being 'new' to the textbooks, experimental evidence indicates that this pathway is ancient, and has been conserved intact throughout its evolution.

Amino Acid Sequence↗

PubMed2005

The interplay between innate and adaptive immunity regulates cancer development.

There is increasing clinical and experimental evidence that inflammation and cancer are causally linked. Much progress has been made in understanding how inflammatory cells contribute to cancer development; however, it is still largely unknown which molecular mechanisms are responsible for initiation and maintenance of chronic inflammation associated with developing neoplasms. This review will discuss how the adaptive and innate immune systems interact during physiological and chronic inflammation, with a focus on studies revealing new insights into the role of adaptive immune cells as important regulators of chronic inflammation-associated carcinogenesis. We will speculate on whether current knowledge about the dysregulated interplay between adaptive and innate immunity during chronic inflammatory disorders might be useful in understanding and targeting the underlying mechanisms of chronic inflammation-associated neoplastic progression.

Animals↗

PubMed2003

Measles virus infection results in suppression of both innate and adaptive immune responses to secondary bacterial infection.

Among infectious agents, measles virus (MV) remains a scourge responsible for 1 million deaths per year and is a leading cause of childhood deaths in developing countries. Although MV infection itself is not commonly lethal, MV-induced suppression of the immune system results in a greatly increased susceptibility to opportunistic bacterial infections that are largely responsible for the morbidity and mortality associated with this disease. Despite its clinical importance, the underlying mechanisms of MV-induced immunosuppression remain unresolved. To begin to understand the basis of increased susceptibility to bacterial infections during MV infection, we inoculated transgenic mice expressing the MV receptor, CD46, with MV and Listeria monocytogenes. We found that MV-infected mice were more susceptible to infection with Listeria and that this corresponded with significantly decreased numbers of macrophages and neutrophils in the spleen and substantial defects in IFN-gamma production by CD4(+) T cells. The reduction in CD11b(+) macrophages and IFN-gamma-producing T cells was due to reduced proliferative expansion and not to enhanced apoptosis or to altered distribution of these cells between spleen, blood, and the lymphatic system. These results document that MV infection can suppress both innate and adaptive immune responses and lead to increased susceptibility to bacterial infection.

Animals↗

PubMed2006

Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function.

Trafficking of dendritic cells (DCs) to peripheral tissues and to secondary lymphoid organs depends on chemokines and lipid mediators. Here, we show that bone marrow-derived DCs (BM-DCs) express functional leukotriene B4 (LTB4) receptors as observed in dose-dependent chemotaxis and calcium mobilization responses. LTB4, at low concentrations, promoted the migration of immature and mature DCs to CCL19 and CCL21, which was associated with a rapid (30-minute) increase of CCR7 expression at the membrane level. At longer incubation times (6 hours), gene array analysis revealed a promoting role of LTB4, showing a significant increase of CCR7 and CCL19 mRNA levels. BM-DCs cultured from BLT1-/- or BLT1/2-/- mice showed a normal phenotype, but in vivo BLT1/2-/-DCs showed dramatic decrease in migration to the draining lymph nodes relative to wild-type (WT) DCs. Consistent with these observations, BLT1/2-/- mice showed a reduced response in a model of 2,4-dinitro-fluorobenzene (DNFB)-induced contact hypersensitivity. Adoptive transfer of 2,4-dinitrobenzene sulfonic acid (DNBS)-pulsed DCs directly implicated the defect in DC migration to lymph node with the defect in contact hypersensitivity. These results provide strong evidence for a role of LTB4 in regulating DC migration and the induction of adaptive immune responses.

Animals↗

PubMed2007

Diabetes induces rapid suppression of adaptive immunity followed by homeostatic T-cell proliferation.

Surprisingly, the effect of acute diabetes on immunity has not been examined in detail. We, herein, show for the first time that untreated acute diabetes causes rapid lymphopenia followed by homeostatic T-cell proliferation. The diabetes-induced lymphopenia was associated with an immunosuppressed state that could be sufficiently strong to allow engraftment of fully allogeneic beta-cells or block rejection of islet transplants. In contrast, homeostatic proliferation and recovery of T-cell numbers were associated with islet rejection. Thus, the timing of islet transplant challenge in relation to diabetes induction was critical in determining whether islets were accepted or rejected. In addition, we tested whether diabetes-related immunosuppression could result in an overestimation of the efficacy of a tolerance-inducing protocol. Consistent with this possibility, a protocol targeting CD40L and ICOS that we have shown induces tolerance in diabetic recipients was unable to induce tolerance in non-diabetic recipients. The data uncover a previously unrecognized suppressive effect of diabetes on adaptive immunity. Furthermore, they suggest that the standard methods of testing new tolerance-inducing protocols in islet transplantation require modification and that diabetes itself can contribute to homeostatic proliferation, a process associated with autoimmunity and a resistance to tolerance induction.

Animals↗

PubMed2005

Isolates of Trichuris muris elicit different adaptive immune responses in their murine host.

The J and S isolates of Trichuris muris have different infection profiles in C57BL/6 mice; J worms are expelled, S worms survive to chronicity. Building on this, the ability of the J and S isolates to survive, and the quality of the immune response induced was explored in three different strains of mouse. The resistant BALB/c mouse mounted a strong Th2 response against both isolates, which were quickly expelled. The susceptible AKR host mounted a Th1 response and retained both isolates. Despite equivalent worm exposure, mesenteric lymph node cells from AKR mice infected with the S isolate produced significantly higher levels of IL-12 and the intestinal mastocytosis was reduced. IgG1 and IgG2a from S-infected AKR mice recognized low molecular weight antigens not recognized by J-infected mice. Differential expulsion kinetics was observed in the slower-responding C57BL/6 strain; J worms were expelled but S isolate worms were retained. Survival of the S isolate was again associated with elevated IL-12 and decreased Th2 responses. In resistant mouse strains, the outcome of infection is thus dominantly influenced by host genetics. However, in the slower-responding host, isolate-derived factors may play a role in shaping the quality of the adaptive immune response, thus influencing parasite survival.

Animals↗

PubMed1998

A further link between innate and adaptive immunity: C3 deposition on antigen-presenting cells enhances the proliferation of antigen-specific T cells.

Murine cells of the B lymphoblastoid line A20 and concanavalin A-elicited peritoneal macrophages are shown to activate and fix C3 fragments covalently when incubated in fresh, autologous serum under conditions allowing the initiation of the alternative complement pathway. For the detection of cell-bound C3, cytofluorimetry was performed using FITC-labeled F(ab')2 fragments of anti-mouse C3. Cell-bound C3 fragments are not internalized or shed by the cells under culture conditions for at least two hours. When the antigen-presenting capacity of serum-treated cells was tested using various antigens and experimental systems, augmentation of the proliferation of antigen-specific T cells was found. This enhancing effect was particularly pronounced at suboptimal antigen doses. The elevation of T cell proliferation induced by C3-opsonized antigen-presenting cells (APC) could be abrogated by F(ab')2 fragments of goat anti-mouse C3, suggesting the involvement of C3 receptors expressed by T cells in the process. Using the 7G6 mAb recognizing murine CR1/CR2, the presence of these complement receptors on activated T cells is demonstrated by cytofluorimetry and immunoprecipitation, as well. These results point to the role of C3 bound to acceptor sites on APC in the facilitation of antigen presentation, providing a further link between innate and adaptive immunity.

Animals↗