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Cell Rep. 2017 Jun 13;19(11):2357-2370. doi: 10.1016/j.celrep.2017.05.052.

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

Author information

1
Laboratory for Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
2
Laboratory for Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK; Faculdade de Medicina da Universidade de Lisboa, Instituto de Medicina Molecular, Av. Professor Egas Moniz, Lisbon 1649-028, Portugal.
3
Immunology Virology and Inflammation Department, Cancer Research Center of Lyon UMR INSERM1052, CNRS 5286 28 rue Laennec, Lyon 69373, Cedex 08, France; Université Lyon 1, Lyon 69000, France; Centre Léon Bérard, Lyon 69008, France; Labex DEVweCAN, Lyon 69008, France.
4
Immunology Virology and Inflammation Department, Cancer Research Center of Lyon UMR INSERM1052, CNRS 5286 28 rue Laennec, Lyon 69373, Cedex 08, France; Université Lyon 1, Lyon 69000, France; Centre Léon Bérard, Lyon 69008, France; Labex DEVweCAN, Lyon 69008, France; TGFβ and Immuno-Evasion Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
5
Laboratory for Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK; Faculdade de Medicina da Universidade de Lisboa, Instituto de Medicina Molecular, Av. Professor Egas Moniz, Lisbon 1649-028, Portugal. Electronic address: marc.veldhoen@medicina.ulisboa.pt.

Abstract

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.

KEYWORDS:

T cell activation; T cell differentiation; T helper cells; Th17 cells; autoimmunity; cell stress; interleukin-17; metabolic stress

PMID:
28614720
PMCID:
PMC5483510
DOI:
10.1016/j.celrep.2017.05.052
[Indexed for MEDLINE]
Free PMC Article

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