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      Symbiont-derived sphingolipids modulate mucosal homeostasis and B cells in teleost fish

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          Abstract

          Symbiotic bacteria and mucosal immunoglobulins have co-evolved for millions of years in vertebrate animals. Symbiotic bacteria products are known to modulate different aspects of the host immune system. We recently reported that Flectobacillus major is a predominant species that lives in the gill and skin mucosal surfaces of rainbow trout ( Oncorhynchus mykiss). F. major is known to produce sphingolipids of a unique molecular structure. Here we propose a role for F. major and its sphingolipids in the regulation of B cell populations in rainbow trout, as well as an essential role for sphingolipids in trout mucosal homeostasis. We found that F. major-specific IgT titers are confined to the gill and skin mucus, whereas F. major-specific IgM titers are only detected in serum. Live F. major cells are able to stimulate sustained IgT expression and secretion in gills. F. major sphingolipids modulate the growth of trout total skin and gill symbiotic bacteria. In vivo systemic administration of F. major sphingolipids changes the proportion of IgT + to IgM + B cells in trout HK. These results demonstrate the key role of the symbiont F. major and its sphingolipids in mucosal homeostasis via the modulation of mucosal and systemic Igs and B cells.

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          Most cited references35

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          An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.

          The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial molecules mediating symbiosis remain undefined. Here we show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and T(H)1/T(H)2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunologic functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine production. These findings provide a molecular basis for host-bacterial symbiosis and reveal the archetypal molecule of commensal bacteria that mediates development of the host immune system.
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            Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

            Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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              How host-microbial interactions shape the nutrient environment of the mammalian intestine.

              Humans and other mammals are colonized by a vast, complex, and dynamic consortium of microorganisms. One evolutionary driving force for maintaining this metabolically active microbial society is to salvage energy from nutrients, particularly carbohydrates, that are otherwise nondigestible by the host. Much of our understanding of the molecular mechanisms by which members of the intestinal microbiota degrade complex polysaccharides comes from studies of Bacteroides thetaiotaomicron, a prominent and genetically manipulatable component of the normal human and mouse gut. Colonization of germ-free mice with B. thetaiotaomicron has shown how this anaerobe modifies many aspects of intestinal cellular differentiation/gene expression to benefit both host and microbe. These and other studies underscore the importance of understanding precisely how nutrient metabolism serves to establish and sustain symbiotic relationships between mammals and their bacterial partners.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                14 December 2016
                2016
                : 6
                : 39054
                Affiliations
                [1 ]Center for Evolutionary and Theoretical Immunology, Department of Biology, University of New Mexico , Albuquerque, NM, USA
                [2 ]Fish Innate Immune System Group, Department of Cell Biology and Histology, Faculty of Biology, Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia , Murcia, Spain
                [3 ]Department of Microbiology, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104, USA
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep39054
                10.1038/srep39054
                5155239
                27966609
                50bbb39c-ef30-4b11-8016-25b8308af5cf
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 22 August 2016
                : 16 November 2016
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