Endocrine self and gut non-self 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: 9.81). 01/2006; 102(49):17729-33. DOI: 10.1073/pnas.0509006102
Source: PubMed

ABSTRACT 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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    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.
    Molecular Immunology 03/2015; 64(1). DOI:10.1016/j.molimm.2014.11.009 · 3.00 Impact Factor
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