RESUMO
Processing of proteins for major histocompatibility complex (MHC) class II-restricted presentation to CD4-positive T lymphocytes occurs after they are internalized by antigen-presenting cells (APCs). Antigenic proteins frequently contain disulfide bonds, and their reduction in the endocytic pathway facilitates processing. In humans, a gamma interferon-inducible lysosomal thiol reductase (GILT) is constitutively present in late endocytic compartments of APCs. Here, we identified the mouse homolog of GILT and generated a GILT knockout mouse. GILT facilitated the processing and presentation to antigen-specific T cells of protein antigens containing disulfide bonds. The response to hen egg lysozyme, a model antigen with a compact structure containing four disulfide bonds, was examined in detail.
Assuntos
Apresentação de Antígeno , Células Apresentadoras de Antígenos/imunologia , Muramidase/imunologia , Oxirredutases/metabolismo , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/enzimologia , Antígenos/química , Antígenos/imunologia , Antígenos/metabolismo , Linhagem Celular , Células Dendríticas/enzimologia , Dissulfetos/química , Epitopos/imunologia , Epitopos/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Hibridomas , Concentração de Íons de Hidrogênio , Imunização , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Muramidase/química , Muramidase/metabolismo , Oxirredutases/química , Oxirredutases/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Conformação Proteica , Dobramento de Proteína , Baço/imunologiaRESUMO
Dendritic cells (DCs) developmentally regulate antigen uptake by controlling their endocytic capacity. Immature DCs actively internalize antigen. However, mature DCs are poorly endocytic, functioning instead to present antigens to T cells. We have found that endocytic downregulation reflects a decrease in endocytic activity controlled by Rho family GTPases, especially Cdc42. Blocking Cdc42 function by Toxin B treatment or injection of dominant-negative inhibitors of Cdc42 abrogates endocytosis in immature DCs. In mature DCs, injection of constitutively active Cdc42 or microbial delivery of a Cdc42 nucleotide exchange factor reactivates endocytosis. DCs regulate endogenous levels of Cdc42-GTP with activated Cdc42 detectable only in immature cells. We conclude that DCs developmentally regulate endocytosis at least in part by controlling levels of activated Cdc42.
Assuntos
Apresentação de Antígeno , Proteínas de Bactérias , Células Dendríticas/imunologia , Endocitose , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Toxinas Bacterianas/farmacologia , Diferenciação Celular , Clatrina , Invaginações Revestidas da Membrana Celular , Regulação para Baixo , Ativação Enzimática , Masculino , Camundongos , Pinocitose , Salmonella typhimurium/imunologia , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidoresRESUMO
Major histocompatibility complex class II (MHC II) molecules capture peptides within the endocytic pathway to generate T cell receptor (TCR) ligands. Immature dendritic cells (DCs) sequester intact antigens in lysosomes, processing and converting antigens into peptide-MHC II complexes upon induction of DC maturation. The complexes then accumulate in distinctive, nonlysosomal MHC II+ vesicles that appear to migrate to the cell surface. Although the vesicles exclude soluble lysosomal contents and antigen-processing machinery, many contain MHC I and B7 costimulatory molecules. After arrival at the cell surface, the MHC and costimulatory molecules remain clustered. Thus, transport of peptide-MHC II complexes by DCs not only accomplishes transfer from late endocytic compartments to the plasma membrane, but does so in a manner that selectively concentrates TCR ligands and costimulatory molecules for T cell contact.
Assuntos
Apresentação de Antígeno , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Muramidase/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Anticorpos Monoclonais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Antígeno B7-2 , Transporte Biológico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Endocitose , Endossomos/imunologia , Endossomos/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Cinética , Ligantes , Lipopolissacarídeos/imunologia , Lisossomos/imunologia , Lisossomos/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Muramidase/imunologia , Fragmentos de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Tiazóis/farmacologia , TiazolidinasRESUMO
A report is presented of a male patient, 5 years, 10 months old, with a palatal cleft complicated by both a tooth and a foreign object in the nasal cavity. The presence of these concurrent conditions contributed to nasal obstruction with associated speech problems, accretions, and chronic rhinorrhea. The importance of a thorough diagnostic work-up and interdisciplinary treatment planning is emphasized.
Assuntos
Corpos Estranhos/complicações , Cavidade Nasal , Obstrução Nasal/etiologia , Pré-Escolar , Fenda Labial/complicações , Fissura Palatina/complicações , Humanos , Masculino , Distúrbios da Fala/etiologia , DenteRESUMO
The diagnosis and management of velopharyngeal insufficiency in a 16-year-old boy with multifocal eosinophilic granuloma (Hand-Schüller-Christian disease) is described. Medical history, speech and velopharyngeal valving information, and the results of clinical management are presented.