Lana Gamire, Ph.D.
University of Hawaii
NIEHS Grant K01ES025434
New research, funded in part by NIEHS, shows that the Th17 lineage of T helper cells — which can cause severe human inflammatory diseases — can also differentiate into regulatory T cells to help resolve inflammation. The instability and plasticity of Th17 might offer a new therapeutic target for inflammatory diseases.
The body’s inflammatory response to infection is beneficial, but unregulated inflammation can contribute to inflammatory diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis. Studies have found that Th17 cells show instability in that they can stop expressing their signature inflammatory cytokine IL-17A. They also show plasticity by expressing cytokines typical of other T-cells. To find out if TH17 cells are merely changing expression of a few cytokines or physiologically undergoing a global genetic reprogramming, the researchers developed new fate-mapping mouse models to track Th17 cells during immune responses.
They found that CD4+ T cells that formerly expressed IL-17A go on to acquire an anti-inflammatory phenotype. During an immune response, the TH17 cells showed a change in their signature transcriptional profile and acquired a strong regulatory capacity. The transcriptional profiles of Th17 cells before and after conversion into regulatory T cells also revealed a role for transforming growth factor (TFG)-beta signaling and the aryl hydrocarbon receptor (AhR) in conversion.
The researchers say that the TH17 cell plasticity might be used to develop new and more effective therapies that restore immune tolerance in chronic inflammatory/autoimmune diseases without the negative side-effects of some systemic immunosuppressive therapies.
Citation: Gagliani N, Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA. 2015. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature; doi:10.1038/nature14452 [Online 29 April 2015].