Turley SJ, Lee JW, Dutton-Swain N, et al. Endocrine self and gut nonself intersect in the pancreatic lymph nodes

Section on Immunology and Immunogenetics, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2006; 102(49):17729-33. DOI: 10.1073/pnas.0509006102
Source: PubMed


The autoimmune cascade that culminates in diabetes initiates within pancreatic lymph nodes (PLNs). Here, we show that developmentally controlled lymphogenesis establishes a preferential trafficking route from the gut to the PLN, where T cells can be activated by antigens drained from the peritoneum and the gastrointestinal tract. Furthermore, intestinal stress modifies the presentation of pancreatic self-antigens in PLNs. The convergence of endocrine and intestinal contents within PLNs has significant implications for type 1 diabetes and may help to explain the link between autoimmune pathogenesis and environmental provocation.

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Available from: Shannon J Turley, Dec 12, 2014
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    • "Gut microbiota has been in recent focus as an environmental factor regulating autoimmunity in type 1 diabetes (Dunne et al., 2014; Karlsson et al., 2013). Potential mechanisms by which microbiota and gut immune responses to microbes could link to diabetic autoimmunity are presentation of gut antigens with molecular mimicry to islet antigens to naïve T cells in pancreatic lymph node (PaLN), or bystander activation of steady-state dendritic cells presenting islet antigens cells in PaLN (Turley et al., 2005). Gut-specific T-cell clones expanding in PaLN could home in pancreatic islets (Hanninen et al., 2007) and, in case of molecular mimicry, participate in islet destruction. "
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    ABSTRACT: Autoimmune destruction of pancreatic islets in the nonobese diabetic (NOD) mouse is driven by T cells recognizing various autoantigens mostly in insulin-producing beta-cells. To investigate if T-cell accumulation in islets during early insulitis is clonally predetermined, we compared the complementarity determining regions (CDR3) of T-cell receptor (TCR)β-chains present in islet-infiltrating T cells in young prediabetic NOD mice. High-throughput sequencing of TCRβ-chain DNA extracted from islets of 7-wk old NOD mice revealed a biased TCRβ-chain repertoire in all mice, as a restricted number of clones (17–36 clones) was highly overrepresented and made over 20% of total islet repertoire in each mouse. Among these clones, various Vβ and Jβ families were present but certain VβJβ combinations such as TRBV19-0-TRBJ2-7 and TRBV13-3-TRBJ2-5 were highly shared between individual mice. On TCRβ-chain CDR sequence level, many islet clones (72–146) were shared between at least two individual mice. None of them was among expanded clones in both, suggesting considerable stochasticity in the interactions between TCR and peptide-MHC, even with a limited range of autoantigens. A comparison of islet-CDR3-sequences with CRD-sequences from other tissues revealed clonal overlap with pancreatic lymph node and gut, but these repertoires did not overlap together. Our results suggest that antigen-specific T cells are expanded in pancreatic lymph node and islets, but different specificities expand in individual mice. Some islet-infiltrating T-cell specificities may have a distinct origin shared with gut-infiltrating T cells.
    Full-text · Article · Mar 2015 · Molecular Immunology
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    • "Utilization of the Salmonella pathogenicity island-2 (SPI2)- encoded type III secretion system (T3SS) [25] for antigen delivery delays antigen expression until the bacteria are taken up by APCs, which increases safety and efficacy. The APCs process and present antigen to other immune cells in the gut and then migrate to other organs [26] [27]. Such vaccines have been shown to be very effective in eliciting both CD8 and CD4 T cell-mediated immune responses in models of infectious diseases and cancer [28] [29]. "
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    ABSTRACT: Type 1 diabetes (T1D) is a metabolic disease that is initiated by the autoimmune destruction of pancreatic insulin-producing beta cells that is accompanied by the development of antigen-specific antibodies and cytotoxic T lymphocytes (CTLs). Several studies have shown that vaccination with diabetic autoantigens provides some protection against this process. In this report we describe a new oral vaccine that utilizes live attenuated Salmonella for simultaneous delivery of autoantigens in conjunction with immunomodulatory cytokine genes to immune cells in the gut mucosa. Recent data showed that live attenuated Salmonella is a safe, simple and effective vector for expression of antigens and cytokines by antigen-presenting cells (APCs) of gut-associated lymphatic tissue (GALT). This novel strategy was tested by fusion of the diabetic autoantigen preproinsulin with Salmonella secretory effector protein (SseF) of pathogenicity island-2 (SPI2). In this way the autoantigen is only expressed inside the host immune cells and translocated to the host cell cytosol. In addition Salmonella was used to deliver the gene for the immunomodulatory cytokine transforming growth factor beta (TGFβ) for host cell expression. Oral co-vaccination of 8 week-old non-obese diabetic (NOD) mice with three weekly doses of both the autoantigen and cytokine significantly reduced the development of diabetes, improved the response to glucose challenge, preserved beta cell mass, and reduced the severity of insulitis compared with controls and autoantigen alone. Combination therapy also resulted in increased circulating levels of IL10 four weeks post-vaccination and IL2 for 12 weeks post-vaccination, but without effect on proinflammatory cytokines IL6, IL12(p70), IL17 and IFNγ. However, in non-responders there was a significant rise in IL12 compared with responders. Future studies will examine the mechanism of this vaccination strategy in more detail. In conclusion, Salmonella-based oral vaccines expressing autoantigens combined with imunomodulatory cytokines appears to be a promising therapy for prevention of T1D.
    Full-text · Article · Mar 2014 · Vaccine
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    • "Considering that cells and antigens preferentially home to the PLNs and pancreas after intraperitoneal injection [28], [29], we postulated that the parasite-induced alterations to PLN immune cell populations were most likely initiated at the site of injection. Analyses of cellular populations following the final injection of FhES (at 6 weeks of age) showed that the total number of cells within the peritoneal lavage increased 6 fold compared to PBS treatment (data not shown). "
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    ABSTRACT: Infections with helminth parasites prevent/attenuate auto-inflammatory disease. Here we show that molecules secreted by a helminth parasite could prevent Type 1 Diabetes (T1D) in nonobese diabetic (NOD) mice. When delivered at 4 weeks of age (coincident with the initiation of autoimmunity), the excretory/secretory products of Fasciola hepatica (FhES) prevented the onset of T1D, with 84% of mice remaining normoglycaemic and insulitis-free at 30 weeks of age. Disease protection was associated with suppression of IFN-γ secretion from autoreactive T cells and a switch to the production of a regulatory isotype (from IgG2a to IgG1) of autoantibody. Following FhES injection, peritoneal macrophages converted to a regulatory M2 phenotype, characterised by increased expression levels of Ym1, Arg-1, TGFβ and PD-L1. Expression of these M2 genetic markers increased in the pancreatic lymph nodes and the pancreas of FhES-treated mice. In vitro, FhES-stimulated M2 macrophages induced the differentiation of Tregs from splenocytes isolated from naïve NOD mice. Collectively, our data shows that FhES contains immune-modulatory molecules that mediate protection from autoimmune diabetes via the induction and maintenance of a regulatory immune environment.
    Full-text · Article · Jan 2014 · PLoS ONE
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