ABSTRACT
The production of IFN-γ is crucial for control of multiple enteric infections, but its impact on intestinal epithelial cells (IEC) is not well understood. Cryptosporidium parasites exclusively infect epithelial cells and the ability of interferons to activate the transcription factor STAT1 in IEC is required for parasite clearance. Here, the use of single cell RNA sequencing to profile IEC during infection revealed an increased proportion of mid-villus enterocytes during infection and induction of IFN-γ-dependent gene signatures that was comparable between uninfected and infected cells. These analyses were complemented by in vivo studies, which demonstrated that IEC expression of the IFN-γ receptor was required for parasite control. Unexpectedly, treatment of Ifng-/- mice with IFN-γ showed the IEC response to this cytokine correlates with a delayed reduction in parasite burden but did not affect parasite development. These data sets provide insight into the impact of IFN-γ on IEC and suggest a model in which IFN-γ signalling to uninfected enterocytes is important for control of Cryptosporidium.
Subject(s)
Cryptosporidiosis , Interferon-gamma , Intestinal Mucosa , Mice, Knockout , Animals , Interferon-gamma/metabolism , Interferon-gamma/immunology , Cryptosporidiosis/immunology , Cryptosporidiosis/parasitology , Mice , Intestinal Mucosa/parasitology , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Cryptosporidium , Epithelial Cells/parasitology , Epithelial Cells/metabolism , Epithelial Cells/immunology , Enterocytes/parasitology , Enterocytes/metabolism , Enterocytes/immunology , Mice, Inbred C57BL , Interferon gamma Receptor , STAT1 Transcription Factor/metabolism , Receptors, Interferon/metabolism , Receptors, Interferon/genetics , Signal TransductionABSTRACT
Las células dendríticas son las células profesionales presentadoras de antígenos más potentes que existen y, tras realizar la presentación antigénica, controlan el tipo de respuesta inmune que se establecerá (proinflamatoria/reguladora), así como su localización. Debido a su gran plasticidad y capacidad de maduración en respuesta a señales de peligro locales derivadas de la inmunidad innata, las células dendríticas son un elemento clave en la conexión entre la inmunidad innata y las respuestas de la inmunidad adaptativa. En el intestino, las células dendríticas controlan los mecanismos de la tolerancia inmunológica frente a los antígenos de la dieta y/o la flora comensal, a la vez que son capaces de iniciar una respuesta inmunológica activa en presencia de un patógeno invasor. Las células dendríticas son pues muy eficientes en controlar el delicado balance entre tolerancia/inmunidad en un ambiente tan cargado de antígenos como es el intestino, y cualquier factor que las afecte puede tener repercusiones en su funcionalidad, pudiendo en última instancia desarrollarse patologías intestinales como la enfermedad celiaca o las enfermedades inflamatorias intestinales. En esta revisión sintetizaremos nuestro conocimiento de las células dendríticas del intestino humano, su capacidad para expresar e inducir marcadores de migración, los diversos factores ambientales que modulan sus propiedades, los diferentes subtipos de células dendríticas que nos encontramos en el intestino y los problemas derivados de su estudio incluyendo sus diferentes estrategias de identificación, las diferencias entre humanos y modelos murinos y sus variaciones fenotípicas a lo largo del tracto gastrointestinal (AU)
Dendritic cells are the most potent, professional antigen-presenting cells in the body; following antigen presentation they control the type (proinflammatory/regulatory) of immune response that will take place, as well as its location. Given their high plasticity and maturation ability in response to local danger signals derived from innate immunity, dendritic cells are key actors in the connection between innate immunity and adaptive immunity responses. In the gut dendritic cells control immune tolerance mechanisms against food and/or commensal flora antigens, and are also capable of initiating an active immune response in the presence of invading pathogens. Dendritic cells are thus highly efficient in controlling the delicate balance between tolerance and immunity in an environment so rich in antigens as the gut, and any factor involving these cells may impact their function, ultimately leading to the development of bowel conditions such as celiac disease or inflammatory bowel disease. In this review we shall summarize our understanding of human intestinal dendritic cells, their ability to express and induce migration markers, the various environmental factors modulating their properties, their subsets in the gut, and the problems entailed by their study, including identification strategies, differences between humans and murine models, and phenotypical variations along the gastrointestinal tract (AU)
Subject(s)
Humans , Male , Female , Dendritic Cells/immunology , Dendritic Cells , Immunity, Mucosal , Immunity, Mucosal/immunology , Immunity, Mucosal/physiology , Celiac Disease/immunology , Cytokines , Oxidative Stress/immunology , Immunoglobulin A, Secretory/physiology , Enterocytes/immunology , Immunomodulation/immunology , Immunomodulation/physiologyABSTRACT
The enterocyte brush border of the small intestine is a highly specialized membranedesigned to function both as a high capacity digestive/absorptive surface ofdietary nutrients and a permeability barrier towards lumenal pathogens. It is characterizedby an unusually high content of glycolipids (~30% of the total microvillarmembrane lipid), enabling the formation of liquid ordered microdomains, betterknown as lipid rafts. The glycolipid rafts are stabilized by galectin-4, a 36 kDa divalentlectin that cross-links galactosyl (and other carbohydrate) residues present onmembrane lipids and several brush border proteins, including some of the majorhydrolases. These supramolecular complexes are further stabilized by intelectin, a 35kDa trimeric lectin that also functions as an intestinal lactoferrin receptor. As a result,brush border hydrolases, otherwise sensitive to pancreatic proteinases, are protectedfrom untimely release into the gut lumen. Finally, anti-glycosyl antibodies, synthesizedby plasma cells locally in the gut, are deposited on the brush border glycolipidrafts, protecting the epithelium from lumenal pathogens that exploit lipid rafts asportals for entry to the organism (AU)
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Subject(s)
Animals , Antibodies/isolation & purification , Enterocytes/immunology , Glycoproteins/immunology , Intestine, Small/metabolism , Membrane Microdomains/immunology , Microvilli/immunology , Galectin 4/analysis , Glycolipids/chemistry , Enterocytes/classification , Enterocytes/metabolism , Glycoproteins/metabolism , Membrane Microdomains/metabolism , Microvilli/chemistry , Microvilli/metabolism , Galectin 4/metabolism , Microvilli/ultrastructureABSTRACT
La mayoría de los antígenos que entran en contacto con el sistema inmune durante la vida de un ser vivo lo hacen a través de la superficie de la mucosa de los tractos respiratorio, gastrointestinal y urogenital. Ocupan una superficie de 400 m2 y forman el área de mayor tamaño en contacto directo con el ambiente externo. Las mucosas separan el ambiente externo del ambiente interno, estéril, y representan una primera línea de defensa. Esta barrera está en contacto tanto con patógenos que han desarrollado mecanismos eficaces para la colonización de epitelios e invasión de mucosas, como con antígenos inocuos, tales como comida, o la flora bacteriana comensal. En el primer caso se necesita una respuesta inmune eficaz y robusta, mientras que en el segundo se requiere una respuesta caracterizada por ignorancia o supresión activa. En estas condiciones, las mucosas han desarrollado un complejo sistema inmune, con características anatómicas y funcionales particulares, capaz de generar rigurosas respuestas frente a antígenos patogénicos, mientras mantiene una situación de ignorancia o supresión activa frente a antígenos no patogénicos (AU)