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2.
PLoS One ; 8(9): e75321, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24086507

RESUMO

Control of parasite replication exerted by MHC class I restricted CD8+ T-cells in the liver is critical for vaccination-induced protection against malaria. While many intracellular pathogens subvert the MHC class I presentation machinery, its functionality in the course of malaria replication in hepatocytes has not been characterized. Using experimental systems based on specific identification, isolation and analysis of human hepatocytes infected with P. berghei ANKA GFP or P. falciparum 3D7 GFP sporozoites we demonstrated that molecular components of the MHC class I pathway exhibit largely unaltered expression in malaria-infected hepatocytes until very late stages of parasite development. Furthermore, infected cells showed no obvious defects in their capacity to upregulate expression of different molecular components of the MHC class I machinery in response to pro-inflammatory lymphokines or trigger direct activation of allo-specific or peptide-specific human CD8+ T-cells. We further demonstrate that ectopic expression of circumsporozoite protein does not alter expression of critical genes of the MHC class I pathway and its response to pro-inflammatory cytokines. In addition, we identified supra-cellular structures, which arose at late stages of parasite replication, possessed the characteristic morphology of merosomes and exhibited nearly complete loss of surface MHC class I expression. These data have multiple implications for our understanding of natural T-cell immunity against malaria and may promote development of novel, efficient anti-malaria vaccines overcoming immune escape of the parasite in the liver.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Genes MHC Classe I/imunologia , Hepatócitos/imunologia , Malária/imunologia , Plasmodium/crescimento & desenvolvimento , Primers do DNA/genética , Genes MHC Classe I/genética , Hepatócitos/parasitologia , Humanos , Malária/metabolismo , Vacinas Antimaláricas/imunologia , Proteínas de Protozoários/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reprodução/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
J Cell Mol Med ; 16(1): 129-41, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21342435

RESUMO

The syntaxin 11 (STX11) gene is mutated in a proportion of patients with familial haemophagocytic lymphohistiocytosis (FHL) and exocytosis of cytotoxic granules is impaired in STX11-deficient NK cells. However, the subcellular localization, regulation of expression and molecular function of STX11 in NK cells and other cytotoxic lymphocytes remain unknown. Here we demonstrate that STX11 expression is strictly controlled by several mechanisms in a cell-type-specific manner and that the enzymatic activity of the proteasome is required for STX11 expression in NK cells. In resting NKL cells, STX11 was localized in the cation-dependent mannose-6-phosphate receptor (CD-M6PR)-containing compartment, which was clearly distinct from cytotoxic granules or Rab27a-expressing vesicles. These subcellular structures appeared to fuse at the contact area with NK-sensitive target cells as demonstrated by partial colocalization of STX11 with perforin and Rab27a. Although STX11-deficent allo-specific cytotoxic T-lymphocytes efficiently lysed target cells and released cytotoxic granules, they exhibited a significantly lower extent of spontaneous association of perforin with Rab27a as compared with STX11-expressing T cells. Thus, our results suggest that STX11 promotes the fusion of Rab27a-expressing vesicles with cytotoxic granules and reveal an additional level of complexity in the spatial/temporal segregation of subcellular structures participating in the process of granule-mediated cytotoxicity.


Assuntos
Grânulos Citoplasmáticos/metabolismo , Sinapses Imunológicas/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Proteínas Qa-SNARE/metabolismo , Linhagem Celular , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Perforina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Qa-SNARE/genética , Frações Subcelulares/metabolismo , Linfócitos T Citotóxicos/imunologia , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTP
4.
J Biol Chem ; 282(42): 30346-56, 2007 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-17699524

RESUMO

Polysialic acid (PSA) is a unique linear homopolymer of alpha2,8-linked sialic acid that has been identified as a posttranslational modification on only five mammalian proteins. Studied predominantly on neural cell adhesion molecule (NCAM) during development of the vertebrate nervous system, PSA modulates cell interactions mediated by NCAM and other adhesion molecules. An isoform of NCAM (CD56) on natural killer (NK) cells is the only protein known to be polysialylated in cells of the immune system, yet the function of PSA in NK cells remains unclear. We show here that neuropilin-2 (NRP-2), a receptor for the semaphorin and vascular endothelial growth factor families in neurons and endothelial cells, respectively, is expressed on the surface of human dendritic cells and is polysialylated. Expression of NRP-2 is up-regulated during dendritic cell maturation, coincident with increased expression of ST8Sia IV, one of the key enzymes of PSA biosynthesis, and with the appearance of PSA on the cell surface. PSA on NRP-2 is resistant to digestion with peptide N-glycosidase F but is sensitive to release under alkaline conditions, suggesting that PSA chains are added to O-linked glycans of NRP-2. Removal of polysialic acid from the surface of dendritic cells or binding of NRP-2 with specific IgG promoted dendritic cell-induced activation and proliferation of T lymphocytes. Thus, this newly recognized polysialylated protein on the surface of dendritic cells influences dendritic cell-T lymphocyte interactions through one or more of its distinct extracellular domains.


Assuntos
Comunicação Celular/fisiologia , Células Dendríticas/metabolismo , Neuropilina-2/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Ácidos Siálicos/metabolismo , Linfócitos T/metabolismo , Anticorpos/imunologia , Anticorpos/farmacologia , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Endoteliais/citologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Moléculas de Adesão de Célula Nervosa/imunologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Neurônios/citologia , Neurônios/imunologia , Neuropilina-2/imunologia , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/química , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/farmacologia , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ácidos Siálicos/imunologia , Sialiltransferases/imunologia , Sialiltransferases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
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