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A Negative Feedback Loop Mediated by STAT3 Limits Human Th17 Responses

Lookup NU author(s): Harriet Purvis, Dr Amy Anderson, Professor David Young, Professor John Isaacs, Dr Catharien Hilkens

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Abstract

The transcription factor STAT3 is critically required for the differentiation of Th17 cells, a T cell subset involved in various chronic inflammatory diseases. In this article, we report that STAT3 also drives a negative-feedback loop that limits the formation of IL-17- producing T cells within a memory population. By activating human memory CD4(+)CD45R0(+) T cells at a high density (HiD) or a low density (LoD) in the presence of the pro-Th17 cytokines IL-1 beta, IL-23, and TGF-beta, we observed that the numbers of Th17 cells were significantly higher under LoD conditions. Assessment of STAT3 phosphorylation revealed a more rapid and stronger STAT3 activation in HiD cells than in LoD cells. Transient inhibition of active STAT3 in HiD cultures significantly enhanced Th17 cell numbers. Expression of the STAT3-regulated ectonucleotidase CD39, which catalyzes ATP hydrolysis, was higher in HiD, than in LoD, cell cultures. Interestingly, inhibition of CD39 ectonucleotidase activity enhanced Th17 responses under HiD conditions. Conversely, blocking the ATP receptor P2X7 reduced Th17 responses in LoD cultures. These data suggest that STAT3 negatively regulates Th17 cells by limiting the availability of ATP. This negative-feedback loop may provide a safety mechanism to limit tissue damage by Th17 cells during chronic inflammation. Furthermore, our results have relevance for the design of novel immunotherapeutics that target the STAT3-signaling pathway, because inhibition of this pathway may enhance, rather than suppress, memory Th17 responses.


Publication metadata

Author(s): Purvis HA, Anderson AE, Young DA, Isaacs JD, Hilkens CMU

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2014

Volume: 193

Issue: 3

Pages: 1142-1150

Print publication date: 01/08/2014

Online publication date: 27/06/2014

Acceptance date: 26/05/2014

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: http://dx.doi.org/10.4049/jimmunol.1302467

DOI: 10.4049/jimmunol.1302467


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