Cellular Stress in the Context of an Inflammatory Environment Supports TGF-β-Independent T Helper-17 Differentiation

Publication date: 13 June 2017
Source:Cell Reports, Volume 19, Issue 11
Author(s): Verena Brucklacher-Waldert, Cristina Ferreira, Marisa Stebegg, Olivier Fesneau, Silvia Innocentin, Julien C. Marie, Marc Veldhoen
T helper-17 (Th17) cells are associated with inflammatory disorders and cancer. We report that environmental conditions resulting in cellular stress, such as low oxygen, glucose, and isotonic stress, particularly enhance the generation of Th17 cells. Pharmacological inhibition of cell stress reduces Th17 cell differentiation while stress inducers enhance the development of Th17 cells. The cellular stress response results in Th17 cell development via sustained cytoplasmic calcium levels and, in part, XBP1 activity. Furthermore, in an inflammatory environment, conditions resulting in cell stress can bring about de novo Th17 cell differentiation, even in the absence of transforming growth factor β (TGF-β) signaling. In vivo, cell stress inhibition enhances resistance to Th17-mediated autoimmunity while stress-exposed T cells enhance disease severity. Adverse metabolic environments during inflammation provide a link between adaptive immunity and inflammation and may represent a risk factor for the development of chronic inflammatory conditions by facilitating Th17 cell differentiation.

Graphical abstract

Teaser

Brucklacher-Waldert et al. show how environmental conditions resulting in cellular stress, such as low metabolite levels, specifically enhance Th17 cell differentiation. Under inflammatory conditions, this stress can substitute for TGF-β signaling resulting in de novo Th17 cell differentiation.


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