Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells. J. Exp. Med. 208, 125-134

Lymphoid Tissue Development Unit, Institut Pasteur, 75724 Paris, France.
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2011; 208(1):125-134. DOI: 10.1084/jem.20100052
Source: PubMed


The programmed development of lymph nodes and Peyer’s patches during ontogeny requires lymphoid tissue inducer (LTi) cells
that express the nuclear hormone receptor RORγt. After birth, LTi cells in the intestine cluster into cryptopatches, the precursors
of isolated lymphoid follicles (ILFs), which are induced to form by symbiotic bacteria and maintain intestinal homeostasis.
We show that in RORγt-deficient mice, which lack LTi cells, programmed lymphoid tissues, ILFs, and Th17 cells, bacterial containment
requires the generation of large numbers of tertiary lymphoid tissues (tLTs) through the activity of B cells. However, upon
epithelial damage, these mice develop severe intestinal inflammation characterized by extensive recruitment of neutrophils
and IgG+ B cells, high expression of activation-induced deaminase in tLTs, and wasting disease. The pathology was prevented by antibiotic
treatment or inhibition of lymphoid tissue formation and was significantly decreased by treatment with intravenous immunoglobulin
G (IVIG). Our data show that intestinal immunodeficiency, such as an absence in RORγt-mediated proinflammatory immunity, can
be compensated by increased lymphoid tissue genesis. However, this comes at a high cost for the host and can lead to a deregulated
B cell response and aggravated inflammatory pathology.

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Available from: Caspar Ohnmacht, Oct 01, 2015
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    • "This could be due to a deleterious effect of the lipotoxicity induced by the HFD. In addition to the lipotoxicity, the changes in gut microbiota induced by the HFD (Cani et al., 2008) could lead to an immunological stress in RORgt À/À mice, which lack secondary lymphoid organs, which has previously been associated with excessive bacterial burden leading to death (Lochner et al., 2011). This important phenotype is still under investigation. "
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    ABSTRACT: A high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 07/2015; 22(1):100-12. DOI:10.1016/j.cmet.2015.06.001 · 17.57 Impact Factor
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    • "Notably, TLT are induced by ectopic expression of LTα or combined LTα and LTβ in multiple organ systems and these studies have provided considerable insight into the biology of these structures (42, 149, 160). There appear to be multiple routes to TLT formation including those induced by RORγt positive cells such as type III innate lymphoid cells (ILC-3) in the gut as well as RORγt independent events (161). Simple ectopic overexpression of several chemokines is sufficient to culminate in TLT formation (152). "
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    ABSTRACT: Lymphoid organs are meeting zones where lymphocytes come together and encounter antigens present in the blood and lymph or as delivered by cells migrating from the draining tissue bed. The exquisite efficiency of this process relies heavily on highly specialized anatomy to direct and position the various players. Gated entry and exit control access to these theaters and reticular networks and associated chemokines guide cells into the proper sections. Lymphoid tissues are remarkably plastic, being able to expand dramatically and then involute upon resolution of the danger. All of the reticular scaffolds and vascular and lymphatic components adapt accordingly. As such, the lymph node (LN) is a wonderful example of a physiologic remodeling process and is potentially a guide to study such elements in pathological settings such as fibrosis, chronic infection, and tumor metastasis. The lymphotoxin/LIGHT axis delivers critical differentiation signals that direct and hone differentiation of both reticular networks and the vasculature. Considerable progress has been made recently in understanding the mesenchymal differentiation pathways leading to these specialized networks and in the remodeling that occurs in reactive LNs. In this article, we will review some new advances in the area in terms of developmental, differentiation, and maintenance events mediated by this axis.
    Frontiers in Immunology 02/2014; 5:47. DOI:10.3389/fimmu.2014.00047
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    • "Eberl and colleagues identified that mice deficient in RORgt exhibited elevated titers of serum immunoglobulin G (IgG) specific for intestinal commensal bacteria in the steady state (Lochner et al., 2011), indicative of impaired intestinal barrier function and dissemination of commensal bacteria to peripheral tissues. Following induction of epithelial damage with DSS administration, RORgt-deficient mice developed hyperactive B cells that promoted commensal bacteria-dependent intestinal pathology and wasting disease (Lochner et al., 2011). Supporting this, mice deficient in CX 3 CR1 + phagocytes, which are critical for optimal IL-22 responses from RORgt + ILCs, exhibit increased translocation of commensal bacteria to the mesenteric lymph node (mLN) and susceptibility to DSS-induced inflammation (Manta et al., 2012; Medina-Contreras et al., 2011). "
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    ABSTRACT: The mammalian intestine harbors trillions of beneficial commensal bacteria that are essential for the development of the immune system and for maintenance of physiologic processes in multiple organs. However, numerous chronic infectious, inflammatory, and metabolic diseases in humans have been associated with alterations in the composition or localization of commensal bacteria that result in dysregulated host-commensal bacteria relationships. The mammalian immune system plays an essential role in regulating the acquisition, composition, and localization of commensal bacteria in the intestine. Emerging research has implicated innate lymphoid cells (ILCs) as a critical immune cell population that orchestrates some of these host-commensal bacteria relationships that can impact immunity, inflammation, and tissue homeostasis in the intestine. This review will discuss reciprocal interactions between intestinal commensal bacteria and ILCs in the context of health and disease.
    Immunity 10/2012; 37(4):601-10. DOI:10.1016/j.immuni.2012.10.003 · 21.56 Impact Factor
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