Th17 cells are essential for intestinal homeostasis

11 March 2013

NIMR scientists have shown that Th17 cell plasticity in Peyer’s patches regulates IgA induction. The research is published in Nature Immunology.

Protecting the integrity of the gut barrier and preventing the vast number of bacteria present in the gut from gaining access to peripheral organs helps to prevent not only infections but also chronic inflammatory diseases and cancer. Intestinal homeostasis is maintained by the immune system and the barrier function of epithelial cells. A large number of innate and adaptive immune cells reside in mucosal tissues and establish an immunological network to maintain healthy conditions. Amongst the adaptive immune cells, B cells producing immunoglobulin A (IgA) are an important player in the maintenance of homeostasis and mucosal host defenses, while the lamina propria layer of the small intestine is home to a substantial proportion of Th17 cells.

It is known that these intestinal Th17 cells contribute to barrier protection by their secretion of cytokines such as interleukin-17 (IL-17) and IL-22, which in turn induce the expression of antimicrobial peptides by gut epithelial cells. Work from Gitta Stockinger’s lab, in the Division of Molecular Immunology, has now shown that Th17 cells have further beneficial functions in the mucosal environment. The discovery of this novel feature has been facilitated by an IL-17 fate reporter mouse model. Previously measurement of IL-17 production was the only means by which these cells were identifiable, but the new model allows detection of Th17 cells even if they have switched off their hallmark cytokine IL-17 and changed their effector function.

The new research shows that Th17 cells adopt a different effector program in the environment of intestinal Peyer’s patches, which are essential lymphoid organs for the generation of T cell-dependent immunoglobulin A production. In Peyer’s patches such Th17 cells switch off their original profile, downregulate production of IL-17 and the Th17 transcription factor RORγt, and acquire a T follicular helper (TFH) phenotype. Such ‘ex-Th17’ cells then induce the development of IgA-producing germinal centre B cells. Mice deficient in Th17 cells fail to generate IgA responses to a challenge with cholera toxin, providing evidence that Th17 cells are the crucial subset required for high affinity T cell-dependent IgA production.

Our data expand the functional repertoire of intestinal Th17. Given the prominent role of Th17 cells in autoimmunity they are obvious targets for therapeutic intervention, but it would seem wise to take care not to disrupt their beneficial functions in maintaining intestinal barrier integrity.

Gitta Stockinger

Click image to view at full-size

eYFP+ cells in Peyers patches.
Courtesy of Anna and Tomasz Zal; MD Anderson Cancer Center, Houston, Texas

Original article

Keiji Hirota, Jan-Eric Turner, Matteo Villa, Joao H. Duarte, Jocelyn Demengeot, Oliver M. Steinmetz and Brigitta Stockinger (2013)

Plasticity of TH17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses

Nature Immunology Epub ahead of print. Publisher abstract.

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