The epithelium that lines the gut is impermeable to macromolecules and microorganisms, except in Peyer's patches (PPs), where the lymphoid follicle-associated epithelium (FAE) contains M cells that transport antigens and microorganisms. A cultured system that reproduces the main characteristics of FAE and M cells was established by cultivation of PP lymphocytes with the differentiated human intestinal cell line Caco-2. Lymphocytes settled into the epithelial monolayer, inducing reorganization of the brush border and a temperature-dependent transport of particles and Vibrio cholerae. This model system could prove useful for intestinal physiology, vaccine research, and drug delivery studies.
Immune surveillance of mucosal surfaces requires the delivery of intact macromolecules and microorganisms across epithelial barriers to organized mucosal lymphoid tissues. Transport, processing and presentation of foreign antigens, as well as local induction and clonal expansion of antigen-specific effector lymphocytes, involves a close collaboration between organized lymphoid tissues and the specialized follicle-associated epithelium. M cells in the follicle-associated epithelium transport foreign macromolecules and microorganisms to antigen-presenting cells within and under the epithelial barrier. Determination of the earliest cellular interactions that occur in and under the follicle-associated epithelium could greatly facilitate the design of effective mucosal vaccines in the future.
Резюме. Микроскладчатые клетки (М-клетки) представляют собой специализированные эпителиальные клетки кишечника, которые инициируют мукозальный иммунный ответ. Эти уникальные фагоцитирующие эпителиальные клетки специализированы для передачи широкого спектра антигенных частиц и микроорганизмов через фолликуло-ассоциированный эпителий (FAE) в лимфоидную ткань, ассоциированную с кишечником (GALT) посредством процесса, называемого трансцитозом. Молекулярная основа поглощения антигена М-клетками была постепенно идентифицирована в последнее десятилетие. Активный отбор проб кишечного антигена инициирует регулируемые иммунные ответы, которые обеспечивают гомеостаз кишечника. Доставка люминальных веществ через эпителий кишечника в иммунную систему является критическим событием в иммунологическом надзоре, что приводит к толерантности к пищевым антигенам и иммунитету к патогенам (например, бактерий, вирусов и паразитов) и их токсинам. Несколько специализированных механизмов транспортирует люминальный антигена через кишечный эпителий. Большой интерес представляет открытие M-клеточно-специфических рецепторов, которые могут выступать в качестве молекулярных мишеней для целевой доставки пероральной вакцины в M-клетки. Недавние исследования показали, что М-клетки используют несколько рецепторов для распознавания и переноса специфических люминальных антигенов. Вакцинация через иммунную систему слизистой оболочки может вызывать эффективные системные иммунные ответы одновременно с иммунитетом слизистой оболочки. Этот обзор имеет целью продемонстрировать молекулы, экспрессируемые на М-клетках и используемые в качестве рецепторов иммунологического надзора для отбора патогенных микроорганизмов в кишечнике, отметить как некоторые патогены используют М-клетки для инфицирования хозяина, и, наконец, показать как эти знания используются для специфического «нацеливания» антигенов на М-клетки, чтобы попытаться повысить эффективность мукозальных вакцин. В последнее время был достигнут существенный прогресс в понимании факторов, влияющих на развитие и функционирование М-клеток.Ключевые слова: антиген, GALT, М-клетки, RANKL, трансцитоз, мукозальный иммунитет, вакцины. Abstract. Microfold cells (M cells) are specialized intestinal epithelial cells that initiate mucosal immune responses. These unique phagocytic epithelial cells are specialized for the transfer of a broad range of particulate antigens and microorganisms across the follicle-associated epithelium (FAE) into the gut-associated lymphoid tissue (GALT) by a process termed transcy-Адрес для переписки: Быков Анатолий Сергеевич 103009, Россия, Москва, ул. Моховая, 11-10, ФГАОУ ВО Первый МГМУ имени И.М. Сеченова.
M cells are distinctive epithelial cells that occur only in the follicle-associated epithelia that overlie organized mucosa-associated lymphoid tissues. They are structurally and functionally specialized for transepithelial transport, delivering foreign antigens and microorganisms to organized lymphoid tissues within the mucosae of the small and large intestines, tonsils and adenoids, and airways. M cell transport is a double-edged sword: Certain pathogens exploit the features of M cells that are intended to promote uptake for the purpose of immunological sampling. Eludication of the molecular architecture of M cell apical surfaces is important for understanding the strategies that pathogens use to exploit this pathway and for utilizing M cell transport for delivery of vaccines to the mucosal immune system. This article reviews the functional and biochemical features that distinguish M cells from other intestinal cell types. In addition it synthesizes the available information on development and differentiation of organized lymphoid tissues and the specialized epithelium associated with these immune inductive sites.
Enteropathogenic bacteria elicit mucosal innate and adaptive immune responses. We investigated whether gut epithelial cells played a role in triggering an adaptive immune response by recruiting dendritic cells (DCs). Immature DCs are selectively attracted by the CCL20 chemokine. The expression of the CCL20 gene in human intestinal epithelial cell lines was up-regulated by pathogenic bacteria, including Salmonella species, but not by indigenous bacteria of the intestinal flora. The Salmonella machinery for epithelial cell invasion was not required for CCL20 gene activation. Flagellin but not the lipopolysaccharide was found to be the Salmonella factor responsible for stimulation of epithelial CCL20 production. CCL20 in turn triggered a specific migration of immature DCs. Our data show that crosstalk between bacterial flagellin and epithelial cells is essential for the recruitment of DCs, a mechanism that could be instrumental to initiate adaptive immune responses in the gut.
Epithelial barriers on mucosal surfaces at different sites in the body differ dramatically in their cellular organization, and antigen sampling strategies at diverse mucosal sites are adapted accordingly. In stratified and pseudostratified epithelia, dendritic cells migrate to the outer limit of the epithelium, where they sample antigens for subsequent presentation in local or distant organized lymphoid tissues. In simple epithelia, specialized epithelial M cells (a phenotype that occurs only in the epithelium over organized lymphoid follicles) deliver samples of foreign material by transepithelial transport from the lumen to organized lymphoid tissues within the mucosa. Certain pathogens exploit the M cell transport process to cross the epithelial barrier and invade the mucosa. Here we review the features of M cells that determine antigen and pathogen adherence and transport into mucosal lymphoid tissues.
The EuroVacc 02 phase I trial has evaluated the safety and immunogenicity of a prime-boost regimen comprising recombinant DNA and the poxvirus vector NYVAC, both expressing a common immunogen consisting of Env, Gag, Pol, and Nef polypeptide domain from human immunodeficiency virus (HIV)-1 clade C isolate, CN54. 40 volunteers were randomized to receive DNA C or nothing on day 0 and at week 4, followed by NYVAC C at weeks 20 and 24. The primary immunogenicity endpoints were measured at weeks 26 and 28 by the quantification of T cell responses using the interferon γ enzyme-linked immunospot assay. Our results indicate that the DNA C plus NYVAC C vaccine regimen was highly immunogenic, as indicated by the detection of T cell responses in 90% of vaccinees and was superior to responses induced by NYVAC C alone (33% of responders). The vaccine-induced T cell responses were (a) vigorous in the case of the env response (mean 480 spot-forming units/106 mononuclear cells at weeks 26/28), (b) polyfunctional for both CD4 and CD8 T cell responses, (c) broad (the average number of epitopes was 4.2 per responder), and (d) durable (T cell responses were present in 70% of vaccinees at week 72). The vaccine-induced T cell responses were strongest and most frequently directed against Env (91% of vaccines), but smaller responses against Gag-Pol-Nef were also observed in 48% of vaccinees. These results support the development of the poxvirus platform in the HIV vaccine field and the further clinical development of the DNA C plus NYVAC C vaccine regimen.
Activation of dendritic cells (DC) by microbial products via Toll-like receptors (TLR) is instrumental in the induction of immunity. In particular, TLR signaling plays a major role in the instruction of Th1 responses. The development of Th2 responses has been proposed to be independent of the adapter molecule myeloid differentiation factor 88 (MyD88) involved in signal transduction by TLRs. In this study we show that flagellin, the bacterial stimulus for TLR5, drives MyD88-dependent Th2-type immunity in mice. Flagellin promotes the secretion of IL-4 and IL-13 by Ag-specific CD4+ T cells as well as IgG1 responses. The Th2-biased responses are associated with the maturation of DCs, which are shown to express TLR5. Flagellin-mediated DC activation requires MyD88 and induces NF-κB-dependent transcription and the production of low levels of proinflammatory cytokines. In addition, the flagellin-specific response is characterized by the lack of secretion of the Th1-promoting cytokine IL-12 p70. In conclusion, this study suggests that flagellin and, more generally, TLR ligands can control Th2 responses in a MyD88-dependent manner.
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