In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 41 ( 2012-10-09)
Kurzfassung:
In total, these studies demonstrate that hypoxia enhances FoxP3 expression and Treg function through at least three distinct mechanisms: ( i ) hypoxia-driven, HIF-1α–dependent, direct transcriptional activation of FoxP3 mRNA; ( ii ) hypoxia-driven, TGF-β–dependent induction of FoxP3-expressing Tregs; and ( iii ) a HIF-1α–dependent mechanism that promotes optimal Treg suppressive function in vitro and in vivo. These studies further indicate that manipulation of HIF signaling in T cells has the potential to either limit or enhance inflammation, offering unique therapeutic options to shape the outcome of inflammation. Given the widespread occurrence of hypoxia in disease, we propose that hypoxia-elicited Tregs are a component of a potent adaptive mechanism to constrain hypoxia-associated inflammation and that disruption of this mechanism may allow unique interventions in hypoxia-associated pathologies characterized by an overly suppressive environment (e.g., solid tumors). To investigate the significance of HIF-1α in regulating the abundance and function of Tregs, we focused on the genetic role of Hif1a specifically within Tregs. In vitro, the inhibitory function of Hif1a -deficient Tregs was reduced. Further, Hif1a -deficient Tregs failed to constrain intestinal inflammation in vivo, in contrast to control Tregs that successfully limited inflammation, affording protection against weight loss and tissue damage in the colon. These data indicate that HIF-1α expressed within Tregs is required for Tregs to exert optimum suppressive function in vivo, particularly in the context of inflammatory bowel disease (Fig. P1). Under hypoxia, stabilization of the hypoxia-inducible factor (HIF)-1α transcription factor induces the expression of multiple genes. In testing whether the transcriptional induction of FoxP3 mRNA by hypoxia was mediated by HIF-1α, we determined that ( i ) the promoter of the FOXP3 gene was transcriptionally activated in hypoxia, ( ii ) HIF-1α protein bound directly to the promoter of the FOXP3 gene in hypoxia, and ( iii ) FoxP3 mRNA synthesis was not induced in cells lacking HIF-1α. These data indicate an HIF-1α−dependent mechanism of FoxP3 induction. Consistent with this transcriptional induction of FoxP3, we found that hypoxic culture increased the abundance of Tregs, defined by FoxP3 protein expression. The enhancement of Treg abundance caused by hypoxia was dependent on transforming growth factor (TGF)-β, a hypoxia-responsive cytokine known to promote FoxP3 expression. Antibody blocking of transforming growth factor-β completely prevented the hypoxic enhancement of Treg abundance during in vitro culture. Notably, these studies found that, in contrast to the findings of recent studies ( 3 , 4 ), hypoxia does not enhance the generation of a subset of proinflammatory Th17 cells unless cells were cultured in the presence of inflammatory cytokines, such as interleukin-6. One cell type frequently present at sites of inflammation is the T lymphocyte, or T cell, an abundant, highly mobile cell type of the immune system. T cells have a tremendous functional capacity, and depending on the specific properties/subsets of T cells at a site of inflammation, T cells can either enhance or constrain inflammation. Different T-cell functions are induced by different transcription factors. To define how hypoxia influences these transcriptional pathways, we tested here the effect of in vitro hypoxic conditions on the expression of transcription factors known to regulate T-cell functional diversification. Notably, T cells exposed to hypoxia had a 10-fold transcriptional up-regulation of the FoxP3 transcription factor, in contrast to 10 other transcription factors whose expression was unchanged upon exposure to hypoxia. The FoxP3 transcription factor is essential for the generation and function of Tregs, a potent anti-inflammatory T-cell subset critical for limiting excessive inflammation ( 2 ). Oxygen is a critical molecule required for survival of a wide range of organisms. When oxygen levels are limiting, a condition referred to as hypoxia, many organisms activate a series of adaptive processes that induce compensatory mechanisms to cope with reduced oxygen. Hypoxia is present in both physiologic and pathologic conditions, such as obesity and cancer ( 1 ). Hypoxia also occurs during inflammation, a coordinated response to a variety of tissue stresses, including infection. Because T lymphocytes, or T cells, are frequently present at sites of inflammatory hypoxia, we sought to define how hypoxia modifies the functional properties of T cells. Here, we showed that hypoxia specifically elicits an anti-inflammatory subset of T cells, referred to as regulatory T cells (Tregs), and that this pathway is important in dampening inflammation.
Materialart:
Online-Ressource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1202366109
Sprache:
Englisch
Verlag:
Proceedings of the National Academy of Sciences
Publikationsdatum:
2012
ZDB Id:
209104-5
ZDB Id:
1461794-8
SSG:
11
SSG:
12
