Wednesday, December 5, 2007

T(H)-17 & Pathology

A colleague writes: "The recent group of papers in Nature Immunology (Stumhofer, Awasthi, and Fitzgerald) concerning TH-17 cells is driven, at least in part, by a question as old as the finding that some T cell lines or clones can cause a model inflammatory disease, EAE: What distinguishes pathogenic T cells in an EAE model from those cells that cannot cause inflammatory disease? With the emergence of the TH1-TH2 paradigm, it became “clear” that the pathogenic cells were of the proinflammatory, TH1 persuasion. This belief was then shaken by experiments using antibodies to, and knockouts of, to the p35 and p40 subunits of IL-12, which revealed that the “key cytokine” leading to pathogenicity was not the TH1-promoting IL-12 itself, but rather IL-23, which shares the p40 subunit. IL-23 was shown to promote a T cell population that produced TNF, IL-6, and IL-17, among other factors. Further study showed that differentiation of T cells toward this new “TH-17” phenotype was most effectively driven by IL-6 in combination with TGF-beta, whereas TGF-beta alone drove expression of Foxp3 and emergence of regulatory T cells.

This new group of papers incorporates a variety of approaches that all lead toward similar conclusions: TH-17s do not constitute a monolithic proinflammatory population, but can be influenced by either IL-27 or the combination of TGF-beta and IL-6 to include cells that secrete IL-10 in addition to IL-17 and that thus suppress inflammatory disease. As the figure from the paper by McGeachy et al. shows, IL-23 and the combination of TGF-beta and IL-6 both induce secretion of IL-17 by T cells during a recall response, but only the IL-23-treated cells cause EAE when transferred into naïve hosts. Other results in this paper and others show that this protection from disease is attributable to IL-10, which is secreted by T cells in response to IL-27 or the TGF-beta/IL-6 combination. These results may point the way to new modalities for steering otherwise harmful autoimmune responses into more benign channels."

McGeachy et al. "TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology." Nat Immunol. 2007 Dec;8(12):1390-7.

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