Dendritic Cells Aid Intestinal Homeostasis and Disease

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Inside our gastrointestinal tract live a family of specialised cells, co-dependent on bacteria and nutrients to send a calming message to the mucosal tissues. They have a number of variations in their make up but they are vital in their role as diplomats, passing sensitive information across the borders to provide a long term peaceful mission and maintain oral tolerance. Essentially they induce either protective immunity to infectious agents or tolerance to innocuous antigens, including food and commensal bacteria. This recent article out in the Journal of Clinical Investigation explores the current understanding of how these cells contribute to health and illness.[1]

Of particular interest are the subset of dendritic cells that promote oral tolerance by their production of Treg cells. The special T cell called CD4+ T cells are subdivided into T helper cells (Th1, Th2, and Th17 cells) and Tregs.

  • Th1 cells are inflammatory cells that release IFN-γ and are involved in immunity against intracellular pathogens, whereas
  • Th2 cells are primarily involved in B cell help as they release B cell growth factors like IL-4.
  • Th17 cells play a critical role in host defense against a variety of bacteria and fungi,[2] but under pathologic conditions such as autoimmunity, Th17 cells exacerbate inflammation.[3]
  • Tregs suppress the function of effector T cells and are thus essential to counteract inflammatory responses.[4]

Inevitably the classification of the different types requires numbers and letters to be conjoined and confuse all readers. For the purpose of this short summary it is best to accept that there are variations in make up and that they have differing levels of effects, but he image below highlights the role of commensal bacteria and in effect probiotics, as well as the need for retinoic acid (RA)or Vitamin A.

Left: CX3CR1+ DCs extend protrusions across the epithelial barrier. These cells also express CD70 and drive the differentiation of Th17 cells via a mechanism dependent on ATP and/or flagellin. CD103+ DCs migrate into the draining MLN, where they promote the conversion of Foxp3+ Tregs via an RA- and TGF-β–dependent mechanism. Tregs also upregulate the expression of the gut-homing marker α4β7. A third population of APCs of non–bone marrow origin expressing CD70+ is required for T cell proliferation directly in the LP. Right: The phenotype of CD103+ LP DCs is conferred by the local microenvironment, in particular by IECs via the release of TGF-β, RA, and — in the human system — TSLP. CD103+ DCs acquire the ability to drive the differentiation of Tregs and to inhibit Th1 and Th17 cell development. Macrophages also limit intestinal inflammation via activation of Tregs and inhibition of the ability of CX3CR1+ DCs to drive Th17 cell development. Macrophages retain full antibactericidal activity.

References


[1] Rescigno M, Di Sabatino A.J Dendritic cells in intestinal homeostasis and disease. Clin Invest. 2009 Sep;119(9):2441-50. doi: 10.1172/JCI39134. Epub 2009 Sep 1. View Full Paper

[2] Dubin, P.J., Kolls, J.K. 2008. Th17 cytokines and mucosal immunity. Immunol. Rev. 226:160-171 View Abstract

[3] Steinman, L. 2008. A rush to judgment on Th17. J. Exp. Med. 205:1517-1522. View Abstract

[4] Coombes, J.L., Powrie, F. 2008. Dendritic cells in intestinal immune regulation. Nat. Rev. Immunol. 8:435-446. View Full Paper

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