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At least 1,711 records · Page 95Linked to original sources

PubMed2004

The Pseudomonas syringae type III effector AvrRpt2 functions downstream or independently of SA to promote virulence on Arabidopsis thaliana.

AvrRpt2, a Pseudomonas syringae type III effector protein, functions from inside plant cells to promote the virulence of P. syringae pv. tomato strain DC3000 (PstDC3000) on Arabidopsis thaliana plants lacking a functional copy of the corresponding RPS2 resistance gene. In this study, we extended our understanding of AvrRpt2 virulence activity by exploring the hypothesis that AvrRpt2 promotes PstDC3000 virulence by suppressing plant defenses. When delivered by PstDC3000, AvrRpt2 suppresses pathogen-related (PR) gene expression during infection, suggesting that AvrRpt2 suppresses defenses mediated by salicylic acid (SA). However, AvrRpt2 promotes PstDC3000 growth on transgenic plants expressing the SA-degrading enzyme NahG, indicating that AvrRpt2 does not promote bacterial virulence by modulating SA levels during infection. AvrRpt2 general virulence activity does not depend on the RPM1 resistance gene, as mutations in RPM1 had no effect on AvrRpt2-induced phenotypes. Transgenic plants expressing AvrRpt2 displayed enhanced susceptibility to PstDC3000 strains defective in type III secretion, indicating that enhanced susceptibility of these plants is not because of suppression of defense responses elicited by other type III effectors. Additionally, avrRpt2 transgenic plants did not exhibit increased susceptibility to Peronospora parasitica and Erysiphe cichoracearum, suggesting that AvrRpt2 virulence activity is specific to P. syringae.

Arabidopsis↗

PubMed2002

CD4 cell priming and tolerization are differentially programmed by APCs upon initial engagement.

Bone marrow-derived APCs present both parenchymal-self and pathogen-derived Ags in a manner that elicits either T cell tolerization or immunity, respectively. To study the parameters that confer tolerogenic vs immunogenic APC function we used an adoptive transfer system in which naive TCR transgenic hemagglutinin (HA)-specific CD4(+) T cells are either tolerized upon encountering HA expressed constitutively as a parenchymal self-Ag (self-HA) or primed to express effector function upon encountering transiently expressed vaccinia-derived HA (viral-HA). When the duration of viral-HA presentation was extended for the period required to elicit tolerization toward self-HA, CD4 cell tolerization to viral-HA did not occur. Furthermore, CD4 cells exhibited both phenotypic as well as functional differences during early stages of tolerization and priming, suggesting that these divergent differentiation processes are programmed soon after the initial APC-CD4 cell interaction. When mice expressing self-HA were infected with an irrelevant vaccinia, CD4 cell tolerization still occurred, indicating that priming vs tolerization cannot be explained by pathogen-induced third parties (i.e., non-APCs) that act directly on CD4 cells. Taken together, these results suggest that CD4 cell tolerization to parenchymal self-Ags and priming to pathogen-derived Ags are initiated by functionally distinct APCs.

Animals↗

PubMed2002

Salmonella pathogenicity island 2 mediates protection of intracellular Salmonella from reactive nitrogen intermediates.

Salmonella typhimurium causes an invasive disease in mice that has similarities to human typhoid. A type III protein secretion system encoded by Salmonella pathogenicity island 2 (SPI2) is essential for virulence in mice, as well as survival and multiplication within macrophages. Reactive nitrogen intermediates (RNI) synthesized by inducible nitric oxide synthase (iNOS) are involved in the control of intracellular pathogens, including S. typhimurium. We studied the effect of Salmonella infection on iNOS activity in macrophages. Immunofluorescence microscopy demonstrated efficient colocalization of iNOS with bacteria deficient in SPI2 but not wild-type Salmonella, and suggests that the SPI2 system interferes with the localization of iNOS and Salmonella. Furthermore, localization of nitrotyrosine residues in the proximity was observed for SPI2 mutant strains but not wild-type Salmonella, indicating that peroxynitrite, a potent antimicrobial compound, is excluded from Salmonella-containing vacuoles by action of SPI2. Altered colocalization of iNOS with intracellular Salmonella required the function of the SPI2-encoded type III secretion system, but not of an individual "Salmonella translocated effector." Inhibition of iNOS increased intracellular proliferation of SPI2 mutant bacteria and, to a lesser extent, of wild-type Salmonella. The defect in systemic infection of a SPI2 mutant strain was partially restored in iNOS(-/-) mice. In addition to various strategies to detoxify RNI or repair damage due to RNI, avoidance of colocalization with RNI is important in adaptation of a pathogen to an intracellular life style.

Animals↗

PubMed1998

Interaction between human interleukin-2-activated natural killer cells and heat-killed germ tube forms of Candida albicans.

Human interleukin-2-activated natural killer (LAK) cells are able to recognize and to bind to both live and heat-killed germ tube forms of Candida albicans, establishing a wide and intimate contact as revealed by electron microscopic observations. Following the interaction, LAK cells are activated: an increased expression of some cytokine mRNA (in particular, TNF-alpha, GM-CSF, and IFN-gamma) has been revealed by RT-PCR and perforin secretion has been suggested by immunofluorescence microscopy. Nonetheless, neither morphological damage or growth inhibition of fungal target cells have been detected. Instead, evident signs of cell damage could be noticed in interacting LAK cells. Moreover, the observation by transmission electron microscopy of LAK cell-germ tube conjugates revealed the presence of apoptotic cells. The analysis of LAK cell cytotoxic activity against DAUDI cells showed that the lymphocytic effector underwent a significant reduction in its lytic capability after the interaction with C. albicans. The results obtained in this in vitro study seem to indicate that in such an interaction LAK cells cannot directly inhibit or kill the fungal pathogen by using their lytic machinery but they secrete those cytokines which have stimulatory effects on phagocytic cells. The ultimate results are the programmed death of LAK cells and the enhancement of the fungicidal activity exerted by competent cells.

Candida albicans↗

PubMed2005

Immune subversion by Helicobacter pylori.

To maintain prolonged colonization of the human gastric mucosa, Helicobacter pylori must avoid both innate and adaptive immune responses. During its long coexistence with humans, it has evolved complex strategies to maintain a mild inflammation of the gastric epithelium while limiting the extent of immune effector activity. Severe disease, associated with bacterial colonization, might reflect loss of this control. Several mechanisms and the bacterial factors involved in immune subversion have, in recent years, been elucidated, thus opening the possibility of a better understanding of the pathogenicity of this microorganism.

Antigen Presentation↗

PubMed1999

Granulocyte and natural killer activity in the elderly.

The deterioration of the immune system in ageing, 'immunosenescence', is thought to contribute to increased morbidity and mortality from infections and possibly autoimmune diseases and cancer. The most profound changes involve effector and immunoregulatory T-cell functions. Immunosenescence appears also to be related to changes in non specific immunity as well. In the present study we have assessed superoxide production, chemotaxis and the expression of the apoptosis-related molecule APO1/Fas (CD95) on neutrophils (PMN) from young and old subjects. Furthermore, we have measured the basal natural killer (NK) activity of young and elderly subjects and we have compared the number of CD16+ cells found in these two groups. We observed a significant decrease age-related both of formation of O2- and chemotaxis whereas no significant correlation between age and the expression of CD95 on granulocyte membrane was demonstrated, suggesting that an increase age-related of CD95-linked apoptosis of PMN should be not an important determinant in the decreased PMN function. We also observed a significant correlation between age and NK activity. The decreased NK cell function was not due to a decreased number of NK cells in effector cell preparations since the number of CD16+ cells was significantly increased in old subjects. In conclusion, our results show that in the elderly there is also a deficit of the aspecific immunity that might play a role in the pathogenic mechanisms of the immunosenescence.

Adult↗

PubMed1999

Regulatory T cells in experimental allergic encephalomyelitis. I. Frequency and specificity analysis in normal and immune rats of a T cell subset that inhibits disease.

We have shown previously that administration of myelin basic protein (MBP)-reactive T cells to naive Lewis rats induces not only autoimmune encephalomyelitis (EAE) but also a near total resistance to subsequent disease. By isolating the effector cells that are responsible for the resistance, we demonstrated that disease protection paralleled with increased numbers of a CD8+ regulatory T cell (RTC) subset and that co-injection of this RTC subset with encephalitogenic T cells aborted the pathogenic activity of the latter cells. Here, we show that a radio-sensitive splenic population of RTC also exists in naive rats that can be recruited and activated to inhibit the onset of secondary episodes of adoptive EAE. In co-transfer experiments, this protective RTC subpopulation can be isolated to neutralize the pathogenic activity of stimulatory MBP-reactive T cells in vivo. We show that the frequency of RTC with specificity for MBP-reactive T cells in naive rats is two orders of magnitude higher than the frequency of MBP-specific precursors, the activity of RTC increases substantially with age and RTC frequencies increase as a consequence of immunization with MBP-reactive cells lines. In specificity studies, we show that RTC isolated from naive rats and RTC from animals primed with one MBP-reactive cell line show cross-reactive responses to a variety of different MBP-reactive T cell lines. However, following repeated stimulation with a given MBP line, these RTC display a more limited, clonotypic response to the selecting line and assume a uniform CD8 phenotype. Finally, functional studies with RTC indicate that proliferative and lytic specificities do not necessarily correlate and that activated rat RTC are especially lytic for a Fas-sensitive murine cell line.

Adoptive Transfer↗

PubMed2006

Autophagy in innate immunity against intracellular bacteria.

Many pathogenic bacteria can invade phagocytic and non-phagocytic cells and colonize them intracellularly, then become disseminated to other cells. The endocytic degradation pathway is thought to be the only prevention against such intracellular pathogens. Autophagy, a fundamental cellular homeostasis pathway that operates with the intracellular degradation/recycling system, causes the turnover of cellular components by delivering portions of the cytoplasm and organelles to lysosomes. Recently, we reported that autophagic degradation is a previously unrecognized effector of host innate immunity. Streptococcus pyogenes (Group A Streptococcus; GAS) successfully enters human epithelial cells via endocytosis. GAS immediately escapes from the endosomes to the cytoplasm and gains a replicative niche, after which GAS in the cytoplasm is trapped in autophagosome-like compartments and degraded upon fusion with lysosomes. This process indicates that autophagy plays a protective role in infectious diseases. We also found that autophagic degradation was induced against Staphylococcus aureus, while methicillin-resistant S. aureus were resistant to autophagic degradation. The present review focuses on the protective function of autophagy against bacterial invasion of cells.

Autophagy↗

PubMed1996

On T cell memory: arguments for antigen dependence.

Memory is a hallmark of the immune system. Considerable progress has been made towards understanding B cell memory, but T cell memory remains poorly understood and its nature is controversial. There is good evidence that B cell memory is driven by antigen, but the antigen dependence of T cell memory is still being debated. For several years we have investigated the nature, duration and antigen dependence of different aspects of CD8+ T cell memory and this review will discuss our findings as well as how and why they differ from some other results. As others, we find that antigen, due to proliferation of antigen-specific T cell clones, induces a shift in the T cell repertoire which remains detectable for years as an elevated cytotoxic T cell precursor frequency (CTLp) in lymphoid organs. Also in the absence of antigen, in vitro assays for T cell memory which invariably isolate memory T cells from these lymphoid organs therefore remain positive. In contrast, immunity against reinfection with a pathogen requires more than just elevated numbers of CTLp in lymphoid organs. Since reinfection usually takes place via peripheral nonlymphoid tissue, these CTLp have to a) efficiently extravasate and patrol through such tissues, and b) be immediately able to exert effector function in case of reinfection. Both functions, require a certain level of activation which critically depends on T cell stimulation by persisting antigen.

Animals↗

PubMed2003

YscP and YscU regulate substrate specificity of the Yersinia type III secretion system.

Pathogenic Yersinia species use a type III secretion system to inhibit phagocytosis by eukaryotic cells. At 37 degrees C, the secretion system is assembled, forming a needle-like structure on the bacterial cell surface. Upon eukaryotic cell contact, six effector proteins, called Yops, are translocated into the eukaryotic cell cytosol. Here, we show that a yscP mutant exports an increased amount of the needle component YscF to the bacterial cell surface but is unable to efficiently secrete effector Yops. Mutations in the cytoplasmic domain of the inner membrane protein YscU suppress the yscP phenotype by reducing the level of YscF secretion and increasing the level of Yop secretion. These results suggest that YscP and YscU coordinately regulate the substrate specificity of the Yersinia type III secretion system. Furthermore, we show that YscP and YscU act upstream of the cell contact sensor YopN as well as the inner gatekeeper LcrG in the pathway of substrate export regulation. These results further strengthen the strong evolutionary link between flagellar biosynthesis and type III synthesis.

Amino Acid Sequence↗

PubMed2005

Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer.

Intracellular pathogens exploit host cell functions to create a replication niche inside eukaryotic cells. The causative agent of Legionnaires' disease, the gamma-proteobacterium Legionella pneumophila, resides and replicates within a modified vacuole of protozoan and mammalian cells. L. pneumophila translocates effector proteins into host cells through the Icm-Dot complex, a specialized type IVB secretion system that is required for intracellular growth. To find out if some effector proteins may have been acquired through interdomain horizontal gene transfer (HGT), we performed a bioinformatic screen that searched for eukaryotic motifs in all open reading frames of the L. pneumophila Philadelphia-1 genome. We found 44 uncharacterized genes with many distinct eukaryotic motifs. Most of these genes contain G+C biases compared to other L. pneumophila genes, supporting the theory that they were acquired through HGT. Furthermore, we found that several of them are expressed and up-regulated in stationary phase in an RpoS-dependent manner. In addition, at least seven of these gene products are translocated into host cells via the Icm-Dot complex, confirming their role in the intracellular environment. Reminiscent of the case with most Icm-Dot substrates, most of the strains containing mutations in these genes grew comparably to the parent strain intracellularly. Our findings suggest that in L. pneumophila, interdomain HGT may have been a major mechanism for the acquisition of determinants of infection.

Amino Acid Motifs↗

PubMed2004

Monitoring of human immunological responses to vaccinia virus.

For the last 30 yr, interest in vaccinia virus immune monitoring has focused on the use of the vaccinia virus as a recombinant vaccine vector and the potential detrimental effect of antivector immunity on subsequent vaccination with a recombinant vaccinia virus. However, interest in this area has intensified after the publication of reports suggesting that smallpox may be a major pathogen selected for bioterrorist activities. Owing to the unacceptably high incidence of complications induced by previous effective smallpox vaccine strains, alternative safer strains (e.g., modified vaccinia Ankara [MVA]) are being assessed for their antigenicity in clinical trials. The exact immune effector mechanism responsible for vaccine-induced protection to smallpox infection has not been fully elucidated, although it is believed that neutralizing antibody plays a major role. This chapter describes a simple enzyme-linked immunosorbent assay (ELISA) to quantify vaccinia virus antibody titer. Additionally, to define serum-neutralizing activity, both a classical plaque reduction assay and a high-throughput 96-well plate method based on reduction of recombinant vaccinia virus expressed beta-galactosidase is described. Furthermore, details are given for a T-cell proliferation assay, primarily for monitoring T-helper CD4 activity and an enzyme-linked immunospot (ELISPOT) assay for CD8 analysis. The use of reliable immunological assays is vital in assessing the potential efficacy of new vaccines to protect against smallpox infection.

Antibodies, Viral↗

PubMed2004

Tolerogenic antigen-presenting cells: regulation of the immune response by TGF-beta-treated antigen-presenting cells.

Tolerogenic antigen-presenting cells (APCs) are attractive agents for the treatment of autoimmune and inflammatory diseases that are mediated, at least in part, by antigen-specific autoreactive T cells. Transforming growth factor-beta (TGF-beta)-treated antigen-presenting cells induce a very potent form of tolerance in mice. One unique feature of this simple and elegant method of tolerance induction is that it is equally potent in both primed and naive mice, an important consideration for the development of a therapy that will be effective against an established disease. In this model, F4/80+ peritoneal exudate cells (macrophages) cultured with antigen and TGF-beta2 injected iv induce populations of regulatory T cells that mediate long-lasting antigen-specific tolerance in mice. The mechanisms that are involved in the induction of tolerance by TGF-beta-treated APCs are very complex and require the interaction of a variety of cell types, as well as soluble and membrane-bound factors. In this review, we summarize the existing data and present new data concerning the induction and effector mechanisms associated with TGF-beta-treated APC-induced tolerance. An understanding of these mechanisms will provide very important information for the design of effective strategies for the treatment of a variety of diseases that are mediated by pathogenic T cells.

Animals↗

PubMed2000

A mechanism for IL-10-mediated diabetes in the nonobese diabetic (NOD) mouse: ICAM-1 deficiency blocks accelerated diabetes.

Neonatal islet-specific expression of IL-10 in nonobese diabetic (NOD) mice accelerates the onset of diabetes, whereas systemic treatment of young NOD mice with IL-10 prevents diabetes. The mechanism for acceleration of diabetes in IL-10-NOD mice is not known. Here we show, by adoptive transfers, that prediabetic or diabetic NOD splenocytes upon encountering IL-10 in the pancreatic islets readily promoted diabetes. This outcome suggests that the compartment of exposure, not the timing, confers proinflammatory effects on this molecule. Moreover, injection of IL-10-deficient NOD splenocytes into transgenic IL-10-NOD.scid/scid mice elicited accelerated disease, demonstrating that pancreatic IL-10 but not endogenous IL-10 is sufficient for the acceleration of diabetes. Immunohistochemical analysis revealed hyperexpression of ICAM-1 on the vascular endothelium of IL-10-NOD mice. The finding suggests that IL-10 may promote diabetes via an ICAM-1-dependent pathway. We found that introduction of ICAM-1 deficiency into IL-10-NOD mice as well as into NOD mice prevented accelerated insulitis and diabetes. Failure to develop insulitis and diabetes was preceded by the absence of GAD65-specific T cell responses. The data suggest that ICAM-1 plays a role in the formation of the "immunological synapse", thereby affecting the generation and/or expansion of islet-specific T cells. In addition, ICAM-1 also played a role in the effector phase of autoimmune diabetes because adoptive transfer of diabetogenic BDC2.5 T cells failed to elicit clinical disease in ICAM-1-deficient IL-10-NOD and NOD mice. These findings provide evidence that pancreatic IL-10 is sufficient to drive pathogenic autoimmune responses and accelerates diabetes via an ICAM-1-dependent pathway.

Adoptive Transfer↗

PubMed1976

Antibody-dependent direct cytotoxicity of human lymphocytes. II. Studies on peripheral blood lymphocytes, synovial fluid cells and sera from patients with rheumatoid arthritis.

Antibody-dependent direct cytotoxicity (ADDC) by human lymphocytes was evaluated in patients with rheumatoid arthritis and normal controls. Purified peripheral blood and synovial fluid lymphocytes mediated normal ADDC when compared to control subjects. No correlation could be obtained between the percentages of T, B and null cells in effector cell populations and the degree of 51Cr released from target cells. Sera from 50% of patients with rheumatoid arthritis inhibited ADDC by normal lymphocytes; the degree of inhibition did not correlate with the titre of IgM rheumatoid factor. The pathogenic implications of these findings are discussed.

Adult↗

PubMed2002

[Mechanism of A/E lesion formation produced by enterohemorrhagic Escherichia coli: O157--role of EspB, Tir and cortactin].

Enterohemorrhagic Escherichia coli(EHEC) belongs to a family of pathogens which cause attaching and effacing(A/E) lesion on target cells. The following event is the alteration of the host intestinal cell cytoskeleton to form a pedestal-like structure. As a result of some recent breakthrough discoveries, EHEC injects effector proteins, EspB and Tir, into the host cells by type III secretion machinery and they modify cellular function and lead the signaling events by its direct binding with cytoskeletal proteins, alpha-catenin and talin. Cortactin is also accumulated to adherent site and involved in EHEC-induced A/E lesion. As a result of those interaction between bacterial effector proteins and host cytoskeletal proteins, EHEC can trigger the rearrangement of the host cell's actin cytoskeleton and induce the A/E lesion.

Bacterial Outer Membrane Proteins↗

PubMedDate not supplied

[Cytotoxic T lymphocytes in cancer and autoimmunity].

Cytotoxic T lymphocytes (CTLs) are cells of the immune system that recognize and kill cells that have been infected with intracellular pathogens, allogenic cells or tumor cells. It has been reported that CTLs participate in the pathogenesis of some autoimmune diseases. After stimulation with the antigen, CTLs undergo an activation process highly regulated, which leads to the cell to acquire an effector or memory function. In this review, we indicate the cellular markers associated with the different stages of CTL-differentiation (naive, memory and effector); we indicate the distinct models of CTLs differentiation; also, the mechanisms of CTLs cytotoxicity are mentioned. Furthermore, we describe the participation of CTLs in cancer and autoimmunity; the implications of CTLs in the progression of these diseases are discussed.

Autoimmunity↗

PubMed1995

Daudi lymphoma killing triggers the programmed death of cytotoxic V gamma 9/V delta 2 T lymphocytes.

A common feature of human V gamma 9/V delta 2 gamma delta T lymphocytes is their ability to kill Daudi lymphoma cells. We show here that during this killing a substantial fraction of cytotoxic gamma delta T cells dies as well. Their death has morphologic, cytometric, and biochemical features of apoptosis and depends on TCR triggering. We suggest that interaction with the target physiologically induces the programmed death of the cytotoxic gamma delta effector. The death of activated gamma delta T cells upon challenge with the relevant Ag may represent a negative feedback mechanism and contribute to explain the limited time span of gamma delta T cell expansions during infectious diseases, even when pathogens are not eliminated and persist in the host.

Apoptosis↗