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1.
Nat Genet ; 39(9): 1092-9, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17694054

RESUMO

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.


Assuntos
População Negra/genética , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Seleção Genética , Alelos , Sequência de Aminoácidos , Sítios de Ligação/genética , Frequência do Gene , Genética Populacional , Antígenos HLA-B/química , Antígenos HLA-B/genética , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Filogenia , Polimorfismo Genético , Estrutura Terciária de Proteína , Receptores KIR3DL1/química , Receptores KIR3DS1/química , Homologia de Sequência de Aminoácidos
2.
Cell Microbiol ; 14(7): 1109-21, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22405091

RESUMO

Neutrophils enter sites of infection, where they can eliminate pathogenic bacteria in an oxidative manner. Despite their predominance in active tuberculosis lesions, the function of neutrophils in this important human infection is still highly controversial. We observed that virulent Mycobacterium tuberculosis survived inside human neutrophils despite prompt activation of these defence cells' microbicidal effectors. Survival of M. tuberculosis was accompanied by necrotic cell death of infected neutrophils. Necrotic cell death entirely depended on radical oxygen species production since chronic granulomatous disease neutrophils were protected from M. tuberculosis-triggered necrosis. More, importantly, the M. tuberculosis ΔRD1 mutant failed to induce neutrophil necrosis rendering this strain susceptible to radical oxygen species-mediated killing. We conclude that this virulence function is instrumental for M. tuberculosis to escape killing by neutrophils and contributes to pathogenesis in tuberculosis.


Assuntos
Viabilidade Microbiana/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Neutrófilos/imunologia , Neutrófilos/microbiologia , Espécies Reativas de Oxigênio/toxicidade , Adolescente , Adulto , Morte Celular , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Virulência , Adulto Jovem
3.
J Immunol ; 184(11): 6043-52, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20427769

RESUMO

Rapid cell-mediated immune responses, characterized by production of proinflammatory cytokines, such as IFN-gamma, can inhibit intraerythrocytic replication of malaria parasites and thereby prevent onset of clinical malaria. In this study, we have characterized the kinetics and cellular sources of the very early IFN-gamma response to Plasmodium falciparum-infected RBCs among human PBMCs. We find that NK cells dominate the early (12-18 h) IFN-gamma response, that NK cells and T cells contribute equally to the response at 24 h, and that T cells increasingly dominate the response from 48 h onward. We also find that although gammadelta T cells can produce IFN-gamma in response to P. falciparum-infected RBCs, they are greatly outnumbered by alphabeta T cells, and thus, the majority of the IFN-gamma(+) T cells are alphabeta T cells and not gammadelta T cells; gammadelta T cells are, however, an important source of TNF. We have previously shown that NK cell responses to P. falciparum-infected RBCs require cytokine and contact-dependent signals from myeloid accessory cells. In this study, we demonstrate that NK cell IFN-gamma responses to P. falciparum-infected RBCs are also crucially dependent on IL-2 secreted by CD4(+) T cells in an MHC class II-dependent manner, indicating that the innate response to infection actually relies upon complex interactions between NK cells, T cells, and accessory cells. We conclude that activation of NK cells may be a critical function of IL-2-secreting CD4(+) T cells and that standard protocols for evaluation of Ag-specific immune responses need to be adapted to include assessment of NK cell activation as well as T cell-derived IL-2.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Eritrócitos/parasitologia , Células Matadoras Naturais/imunologia , Malária Falciparum/imunologia , Receptor Cross-Talk/imunologia , Linfócitos T CD4-Positivos/metabolismo , Separação Celular , Citometria de Fluxo , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-2/biossíntese , Interleucina-2/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Plasmodium falciparum/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Infect Immun ; 79(4): 1647-53, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21282414

RESUMO

Cryptosporidiosis is an important diarrheal disease of humans and neonatal livestock caused by Cryptosporidium spp. that infect epithelial cells. Recovery from Cryptosporidium parvum infection in adult hosts involves CD4(+) T cells with a strong Th1 component, but mechanisms of immunity in neonates are not well characterized. In the present investigation with newborn mice, similar acute patterns of infection were obtained in C57BL/6 wild-type (WT) and T and B cell-deficient Rag2(-/-) mice. In comparison with uninfected controls, the proportion of intestinal CD4(+) or CD8(+) T cells did not increase in infected WT mice during recovery from infection. Furthermore, infection in neonatal WT mice depleted of CD4(+) T cells was not exacerbated. Ten weeks after WT and Rag2(-/-) mice had been infected as neonates, no patent infections could be detected. Treatment at this stage with the immunosuppressive drug dexamethasone produced patent infections in Rag2(-/-) mice but not WT mice. Expression of inflammatory markers, including gamma interferon (IFN-γ) and interleukin-12p40 (IL-12p40), was higher in neonatal WT mice than in Rag2(-/-) mice around the peak of infection, but IL-10 expression was also higher in WT mice. These results suggest that although CD4(+) T cells may be important for elimination of C. parvum, these cells are dispensable for controlling the early acute phase of infection in neonates.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Criptosporidiose/imunologia , Criptosporidiose/patologia , Animais , Animais Recém-Nascidos , Separação Celular , Cryptosporidium parvum/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Eur J Immunol ; 40(2): 396-405, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19950174

RESUMO

Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MPhi. IFN-gamma secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MPhi to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MPhi. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophil-driven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.


Assuntos
Imunidade/imunologia , Interleucina-18/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Análise de Variância , Animais , Quimiocinas/genética , Citocinas/genética , Expressão Gênica , Predisposição Genética para Doença , Interferon gama/metabolismo , Interleucina-18/genética , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Infiltração de Neutrófilos/imunologia , Receptores de Interleucina-18/genética , Receptores de Interleucina-18/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th1/imunologia , Células Th1/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Tuberculose/genética , Tuberculose/microbiologia
6.
J Immunol ; 182(10): 6426-34, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19414796

RESUMO

IFN-gamma emanating from NK cells is an important component of innate defense against infection. In this study, we demonstrate that, following in vitro stimulation of human peripheral blood NK cells with a variety of microbial ligands, CD56(dim) as well as CD56(bright) NK cells contribute to the overall NK cell IFN-gamma response with, for most cell donors, IFN-gamma(+) CD56(dim) NK cells outnumbering IFN-gamma(+) CD56(bright) NK cells. We also observe that the magnitude of the human NK IFN-gamma response to microbial ligands varies between individuals; that the antimicrobial response of CD56(bright), but not CD56(dim), NK cells is highly correlated with that of myeloid accessory cells; and that the ratio of IFN-gamma(+) CD56(dim) to IFN-gamma(+) CD56(bright) NK cells following microbial stimulation differs between individuals but remains constant for a given donor over time. Furthermore, ratios of IFN-gamma(+) CD56(dim) to IFN-gamma(+) CD56(bright) NK cells for different microbial stimuli are highly correlated and the relative response of CD56(dim) and CD56(bright) NK cells is highly significantly associated with killer Ig-like receptor (KIR) genotype. These data reveal an influence of KIR genotype, possibly mediated via NK cell education, on the ability of NK cells to respond to nonviral infections and have implications for genetic regulation of susceptibility to infection in humans.


Assuntos
Antígenos de Bactérias/imunologia , Antígeno CD56/metabolismo , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Receptores KIR/imunologia , Antígeno CD56/imunologia , Citocinas/imunologia , Citometria de Fluxo , Genótipo , Humanos , Interferon gama/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/metabolismo
7.
Cell Microbiol ; 11(9): 1354-64, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19473199

RESUMO

The apicomplexan parasite Cryptosporidium parvum, the agent of cryptosporidiosis, primarily infects and reproduces in enterocytes. Interferon (IFN)-gamma is important for early control of the infection and acts directly on enterocytes to inhibit parasite development, although complete inhibition is not obtained. Addressing this latter observation, an investigation was made of the modulatory effect of C. parvum infection on IFN-gamma-dependent enterocyte gene expression. Initial studies showed that IFN-gamma-induced expression of indoleamine 2, 3 dioxygenase (IDO) mRNA and protein in CMT-93 cells was abrogated by C. parvum infection. Infection also inhibited IDO expression by the human enterocyte cell lines HT29 and Caco-2. Expression of IFN-gamma-inducible genes important in the development of immune responses, including major histocompatibility complex class II and CIITA, was also inhibited by the parasite. Investigating a possible mechanism for these findings, it was shown that infection caused depletion of STAT1alpha protein, a key transcription factor in IFN-gamma signalling. These findings indicate C. parvum interferes with IFN-gamma-dependent gene expression in enterocytes and suggest this activity could be a novel immuno-evasive strategy employed by the parasite.


Assuntos
Cryptosporidium parvum/imunologia , Enterócitos/imunologia , Enterócitos/parasitologia , Regulação da Expressão Gênica , Interferon gama/imunologia , Transdução de Sinais , Animais , Linhagem Celular , Perfilação da Expressão Gênica , Humanos , Fator Gênico 3 Estimulado por Interferon/metabolismo , Camundongos
8.
J Infect Dis ; 200(10): 1548-55, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19821721

RESUMO

Type II interferon (IFN), IFN-gamma, is important in innate immunity to the intestinal protozoan parasite Cryptosporidium species, which infects epithelial cells (enterocytes). This investigation is, to our knowledge, the first to characterize the role of type I IFN in innate immunity to this parasite. Pretreatment of human or murine enterocyte cell lines with IFN-alpha/beta inhibited parasite development, and we identified that a key mechanism of cytokine action was to prevent parasite invasion of enterocytes. IFN-alpha/beta was rapidly expressed by infected murine enterocytes and also by bone marrow-derived dendritic cells that were exposed to live parasites. Treatment of neonatal severe combined immunodeficiency mice with anti-IFN-alpha/beta neutralizing antibodies before infection increased oocyst reproduction, as measured at the peak of infection, and parasite numbers in gut epithelium were also increased 2 days after infection. The latter observation correlated with strong intestinal expression of both IFN-alpha and IFN-beta messenger RNA within 24 h after infection. Treatment with anti-IFN-alpha/beta, however, did not reduce early expression of IFN-gamma. These findings identify a novel early innate host response against Cryptosporidium parvum involving IFN-alpha/beta.


Assuntos
Criptosporidiose/imunologia , Cryptosporidium parvum/imunologia , Enterócitos/imunologia , Imunidade Inata , Interferon-alfa/imunologia , Interferon beta/imunologia , Animais , Células CACO-2 , Enterócitos/parasitologia , Humanos , Interferon-alfa/genética , Interferon beta/genética , Camundongos , RNA Mensageiro
9.
Infect Immun ; 77(11): 5044-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19687195

RESUMO

A gamma interferon (IFN-gamma)-dependent innate immune response operates against the intestinal parasite Cryptosporidium parvum in T- and B-cell-deficient SCID mice. Although NK cells are a major source of IFN-gamma in innate immunity, their protective role against C. parvum has been unclear. The role of NK cells in innate immunity was investigated using Rag2-/- mice, which lack T and B cells, and Rag2-/- gammac-/- mice, which, in addition, lack NK cells. Adult mice of both knockout lines developed progressive chronic infections; however, on most days the level of oocyst excretion was higher in Rag2-/- gammac-/- mice and these animals developed morbidity and died, whereas within the same period the Rag2-/- mice appeared healthy. Neonatal mice of both mouse lines survived a rapid onset of infection that reached a higher intensity in Rag2-/- gammac-/- mice. Significantly, similar levels of intestinal IFN-gamma mRNA were expressed in Rag2-/- and Rag2-/- gammac-/- mice. Also, infections in each mouse line were exacerbated by treatment with anti-IFN-gamma neutralizing antibodies. These results support a protective role for NK cells and IFN-gamma in innate immunity against C. parvum. In addition, the study implies that an intestinal cell type other than NK cells may be an important source of IFN-gamma during infection and that NK cells may have an IFN-gamma-independent protective role.


Assuntos
Criptosporidiose/imunologia , Imunidade Inata , Interferon gama/imunologia , Intestinos/imunologia , Células Matadoras Naturais/imunologia , Animais , Cryptosporidium parvum/imunologia , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Microbes Infect ; 10(9): 995-1004, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18762264

RESUMO

Tuberculosis is the most important bacterial infection world wide. The causative agent, Mycobacterium tuberculosis survives and proliferates within macrophages. Immune mediators such as interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) activate macrophages and promote bacterial killing. IFN-gamma is predominantly secreted by innate cells (mainly natural killer (NK) cells) and by T cells upon instruction by interleukin 12 (IL-12) and IL-18. These cytokines are primarily produced by dendritic cells and macrophages in response to Toll-like receptor (TLR) signalling interaction with tubercle bacilli. These signals also induce pro-inflammatory cytokines (including IL-1beta and TNF-alpha), chemokines and defensins. The inflammatory environment further recruits innate effector cells such as macrophages, polymorphonuclear neutrophils (PMN) and NK cells to the infectious foci. This eventually leads to the downstream establishment of acquired T cell immunity which appears to be protective in more than 90% of infected individuals. Robust innate immune activation is considered an essential prerequisite for protective immunity and vaccine efficacy. However, data published so far provide a muddled view of the functional importance of innate immunity in tuberculosis. Here we critically discuss certain aspects of innate immunity, namely PMN, TLRs and NK cells, as characterised in tuberculosis to date, and their contribution to protection and pathology.


Assuntos
Imunidade Inata , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Humanos , Células Matadoras Naturais/imunologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/fisiologia , Neutrófilos/imunologia , Receptores Toll-Like/imunologia , Tuberculose/fisiopatologia
11.
PLoS Pathog ; 2(12): e118, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17154717

RESUMO

Data from a variety of experimental models suggest that natural killer (NK) cells require signals from accessory cells in order to respond optimally to pathogens, but the precise identity of the cells able to provide such signals depends upon the nature of the infectious organism. Here we show that the ability of human NK cells to produce interferon-gamma in response to stimulation by Plasmodium falciparum-infected red blood cells (iRBCs) is strictly dependent upon multiple, contact-dependent and cytokine-mediated signals derived from both monocytes and myeloid dendritic cells (mDCs). Contrary to some previous reports, we find that both monocytes and mDCs express an activated phenotype following short-term incubation with iRBCs and secrete pro-inflammatory cytokines. The magnitude of the NK cell response (and of the KIR(-) CD56(bright) NK cell population in particular) is tightly correlated with resting levels of accessory cell maturation, indicating that heterogeneity of the NK response to malaria is a reflection of deep-rooted heterogeneity in the human innate immune system. Moreover, we show that NK cells are required to maintain the maturation status of resting mDCs and monocytes, providing additional evidence for reciprocal regulation of NK cells and accessory cells. However, NK cell-derived signals are not required for activation of accessory cells by either iRBCs or bacterial lipolysaccharide. Together, these data suggest that there may be differences in the sequence of events required for activation of NK cells by non-viral pathogens compared to the classical model of NK activation by virus-infected or major histocompatibility complex-deficient cells. These findings have far-reaching implications for the study of immunity to infection in human populations.


Assuntos
Comunicação Celular/fisiologia , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Malária Falciparum/metabolismo , Células Mieloides/fisiologia , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Eritrócitos/parasitologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Interferons/fisiologia , Interleucina-2/fisiologia , Células Matadoras Naturais/imunologia , Lectinas Tipo C , Malária Falciparum/imunologia , Células Mieloides/imunologia , Plasmodium falciparum/imunologia , Plasmodium falciparum/patogenicidade , Transdução de Sinais/fisiologia
12.
Int J Parasitol ; 34(13-14): 1517-28, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15582528

RESUMO

Natural killer (NK) cells are lymphoid cells that mediate significant cytotoxic activity and produce high levels of pro-inflammatory cytokines in response to infection. During viral infection, NK cell cytotoxicity and cytokine production is induced principally by monocyte-macrophage- and dendritic cell-derived cytokines but virally encoded ligands for NK cells are also beginning to be described. NK derived interferon-gamma (IFN-gamma) production is also essential for control of several protozoal infections including toxoplasmosis, trypanosomiasis, leishmaniasis and malaria. The activation of NK cells by protozoan pathogens is also believed to be cytokine-mediated although some recent studies suggest that direct recognition of parasites by NK cells also occurs. Both indirect signalling via accessory cell-derived cytokines and direct signalling, presumably through NK receptors, are needed in order for human malaria parasites (Plasmodium falciparum) to optimally stimulate NK activity.


Assuntos
Células Matadoras Naturais/imunologia , Infecções por Protozoários/imunologia , Humanos , Imunidade Inata , Ativação Linfocitária , Malária/imunologia , Receptores Imunológicos/metabolismo
13.
Eur J Immunol ; 38(3): 680-94, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18266299

RESUMO

The role of Toll-like receptors (TLR) and MyD88 for immune responses to Mycobacterium tuberculosis (Mtb) infection remains controversial. To address the impact of TLR-mediated pathogen recognition and MyD88-dependent signaling events on anti-mycobacterial host responses, we analyzed the outcome of Mtb infection in TLR2/4/9 triple- and MyD88-deficient mice. After aerosol infection, both TLR2/4/9-deficient and wild-type mice expressed pro-inflammatory cytokines promoting antigen-specific T cells and the production of IFN-gamma to similar extents. Moreover, TLR2/4/9-deficient mice expressed IFN-gamma-dependent inducible nitric oxide synthase and LRG-47 in infected lungs. MyD88-deficient mice expressed pro-inflammatory cytokines and were shown to expand IFN-gamma-producing antigen-specific T cells, albeit in a delayed fashion. Only mice that were deficient for MyD88 rapidly succumbed to unrestrained mycobacterial growth, whereas TLR2/4/9-deficient mice controlled Mtb replication. IFN-gamma-dependent restriction of mycobacterial growth was severely impaired only in Mtb-infected MyD88, but not in TLR2/4/9-deficient bone marrow-derived macrophages. Our results demonstrate that after Mtb infection neither TLR2, -4, and -9, nor MyD88 are required for the induction of adaptive T cell responses. Rather, MyD88, but not TLR2, TLR4 and TLR9, is critical for triggering macrophage effector mechanisms central to anti-mycobacterial defense.


Assuntos
Mycobacterium tuberculosis/imunologia , Fator 88 de Diferenciação Mieloide/fisiologia , Receptor 2 Toll-Like/fisiologia , Receptor 4 Toll-Like/fisiologia , Receptor Toll-Like 9/fisiologia , Tuberculose/imunologia , Estruturas Animais/microbiologia , Animais , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica/efeitos dos fármacos , Imunidade Celular/genética , Imunidade Celular/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon gama/metabolismo , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/agonistas , Fator 88 de Diferenciação Mieloide/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/genética , Tuberculose/genética , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
14.
J Immunol ; 175(11): 7466-73, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16301654

RESUMO

Human NK cells can respond rapidly to Plasmodium falciparum-infected RBC (iRBC) to produce IFN-gamma. In this study, we have examined the heterogeneity of this response among malaria-naive blood donors. Cells from all donors become partially activated (up-regulating CD69, perforin, and granzyme) upon exposure to iRBC but cells from only a subset of donors become fully activated (additionally up-regulating CD25, IFN-gamma, and surface expression of lysosomal-associated membrane protein 1 (LAMP-1)). Although both CD56dim and CD56bright NK cell populations can express IFN-gamma in response to iRBC, CD25 and LAMP-1 are up-regulated only by CD56dim NK cells and CD69 is up-regulated to a greater extent in this subset; by contrast, perforin and granzyme A are preferentially up-regulated by CD56bright NK cells. NK cells expressing IFN-gamma in response to iRBC always coexpress CD69 and CD25 but rarely LAMP-1, suggesting that individual NK cells respond to iRBC either by IFN-gamma production or cytotoxicity. Furthermore, physical contact with iRBC can, in a proportion of donors, lead to NK cell cytoskeletal reorganization suggestive of functional interactions between the cells. These observations imply that individuals may vary in their ability to mount an innate immune response to malaria infection with obvious implications for disease resistance or susceptibility.


Assuntos
Eritrócitos/microbiologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Plasmodium falciparum/imunologia , Animais , Antígenos CD/biossíntese , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/imunologia , Doadores de Sangue , Antígenos CD5/biossíntese , Antígenos CD5/imunologia , Comunicação Celular/imunologia , Células Cultivadas , Citometria de Fluxo , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Células Matadoras Naturais/microbiologia , Lectinas Tipo C , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/imunologia , Microscopia Confocal , Perforina , Proteínas Citotóxicas Formadoras de Poros , Receptores de Interleucina-2/biossíntese , Receptores de Interleucina-2/imunologia , Regulação para Cima
15.
Immunity ; 23(3): 287-96, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16169501

RESUMO

Understanding the regulation of immune responses is central for control of autoimmune and infectious disease. In murine models of autoimmunity and chronic inflammatory disease, potent regulatory T lymphocytes have recently been characterized. Despite an explosion of interest in these cells, their relevance to human disease has been uncertain. In a longitudinal study of malaria sporozoite infection via the natural route, we provide evidence that regulatory T cells have modifying effects on blood-stage infection in vivo in humans. Cells with the characteristics of regulatory T cells are rapidly induced following blood-stage infection and are associated with a burst of TGF-beta production, decreased proinflammatory cytokine production, and decreased antigen-specific immune responses. Both the production of TGF-beta and the presence of CD4+CD25+FOXP3+ regulatory T cells are associated with higher rates of parasite growth in vivo. P. falciparum-mediated induction of regulatory T cells may represent a parasite-specific virulence factor.


Assuntos
Proteínas de Ligação a DNA/imunologia , Malária Falciparum/imunologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Antígenos CD4/imunologia , Ensaios Clínicos como Assunto , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead , Humanos , Malária Falciparum/parasitologia , Plasmodium falciparum/imunologia , Receptores de Interleucina-2/imunologia , Linfócitos T/parasitologia , Fator de Crescimento Transformador beta/sangue , Regulação para Cima
16.
EMBO Rep ; 5(7): 698-703, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15205678

RESUMO

AAA proteases are membrane-bound ATP-dependent proteases that are present in eubacteria, mitochondria and chloroplasts and that can degrade membrane proteins. Recent evidence suggests dislocation of membrane-embedded substrates for proteolysis to occur in a hydrophilic environment; however, next to nothing is known about the mechanism of this process. Here, we have analysed the role of the membrane-spanning domains of Yta10 and Yta12, which are conserved subunits of the hetero-oligomeric m-AAA protease in the mitochondria of Saccharomyces cerevisiae. We demonstrate that the m-AAA protease retains proteolytic activity after deletion of the transmembrane segments of either Yta10 or Yta12. Although the mutant m-AAA protease is still capable of processing cytochrome c peroxidase and degrading a peripheral membrane protein, proteolysis of integral membrane proteins is impaired. We therefore propose that transmembrane segments of m-AAA protease subunits have a direct role in the dislocation of membrane-embedded substrates.


Assuntos
Membrana Celular/metabolismo , Metaloendopeptidases/fisiologia , Mitocôndrias/metabolismo , Adenosina Trifosfatases/fisiologia , Trifosfato de Adenosina/metabolismo , Proliferação de Células , Citocromo-c Peroxidase/metabolismo , Eletroforese em Gel de Poliacrilamida , Deleção de Genes , Imunoprecipitação , Metaloendopeptidases/metabolismo , Proteínas Mitocondriais , Mutagênese , Consumo de Oxigênio , Conformação Proteica , Estrutura Terciária de Proteína , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiologia , Temperatura , Fatores de Tempo
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