Glycoantigens Induce Human Peripheral Tr1 Cell Differentiation with Gut-homing Specialization

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(11):8810-8. DOI: 10.1074/jbc.M110.206011
Source: PubMed


The carbohydrate antigen (glycoantigen) PSA from an intestinal commensal bacteria is able to down-regulate inflammatory bowel
disease in model mice, suggesting that stimulation with PSA results in regulatory T cell (Treg) generation. However, mechanisms
of how peripheral human T cells respond and home in response to commensal antigens are still not understood. Here, we demonstrate
that a single exposure to PSA induces differentiation of human peripheral CD4+ T cells into type-Tr1 Tregs. This is in contrast to mouse models where PSA induced the production of Foxp3+ iTregs. The human PSA-induced Tr1 cells are profoundly anergic and exhibit nonspecific bystander suppression mediated by
IL-10 secretion. Most surprisingly, glycoantigen exposure provoked expression of gut homing receptors on their surface. These
findings reveal a mechanism for immune homeostasis in the gut whereby exposure to commensal glycoantigens provides the requisite
information to responding T cells for proper tissue localization (gut) and function (anti-inflammatory/regulatory).

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past several years, there have been remarkable advances in our understanding of how commensal organisms shape host immunity. Although the full cast of immunogenic bacteria and their immunomodulatory molecules remains to be elucidated, lessons learned from the interactions between bacterial zwitterionic polysaccharides (ZPSs) and the host immune system represent an integral step toward better understanding how the intestinal microbiota effect immunologic changes. Somewhat paradoxically, ZPSs, which are found in numerous commensal organisms, are able to elicit both proinflammatory and immunoregulatory responses; both these outcomes involve fine-tuning the balance between T-helper 17 cells and interleukin-10-producing regulatory T cells. In this review, we discuss the immunomodulatory effects of the archetypal ZPS, Bacteroides fragilis PSA. In addition, we highlight some of the opportunities and challenges in applying these lessons in clinical settings.
    Full-text · Article · Jan 2012 · Immunological Reviews
  • [Show abstract] [Hide abstract]
    ABSTRACT: The healthy gut tolerates very large numbers of diverse bacterial species belonging mainly to the Bacteroidetes and Firmicutes phyla. These bacteria normally coexist peacefully with the gut and help maintain immune homeostasis and tolerance. The mechanisms promoting tolerance affect various cell populations, including the epithelial cells lining the gut, resident dendritic cells (DCs), and gut-homing T cells. Gut bacteria also influence multiple signaling pathways from Toll-like receptors to nuclear factor κB and regulate the functionality of DCs and T cells. Several bacterial species have been identified that promote T-cell differentiation, in particular T-helper 17 and T-regulatory cells. Insight into the molecular mechanisms by which bacteria mediate these effects will be very important in identifying new ways of treating intestinal and extra-intestinal immune-mediated diseases. These diseases are increasing dramatically in the human population and require new treatments. It may be possible in the future to identify specific bacterial species or strains that can correct for T-cell imbalances in the gut and promote immune homeostasis, both locally and systemically. In addition, new information describing microbial genomes affords the opportunity to mine for functional genes that may lead to new generation drugs relevant to a range of inflammatory disease conditions.
    No preview · Article · Jan 2012 · Immunological Reviews
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Numerous regulatory programs have been identified that contribute to the restoration of homeostasis at the conclusion of immune responses and to safeguarding against the detrimental effects of chronic inflammation and autoimmune pathology. Malignant cells may usurp these pathways to create immunosuppressive networks that thwart antitumor responses. Herein we review the role of endogenous lectins (C-type lectins, siglecs, and galectins) and specific N- and O-glycans generated by the coordinated action of glycosyltransferases and glycosidases that together promote regulatory signals that control immune cell homeostasis. We also discuss the mechanisms by which glycan-dependent regulatory programs integrate into canonical circuits that amplify or silence immune responses related to autoimmunity and neoplastic disease.
    Full-text · Article · Mar 2012 · Immunity
Show more