TGF-β Promotes Th17 Cell Development through Inhibition of SOCS3

Qin, Hongwei; Wang, Lanfang; Feng, Ting; Elson, Charles O.; Niyongere, Sandrine; Lee, Sun Jung; Reynolds, Stephanie L.; Weaver, Casey T.; Roarty, Kevin; Serra, Rosa; Benveniste, Etty N.; Cong, Yingzi

doi:10.4049/jimmunol.0801986

Cited by 197 publications

(164 citation statements)

References 32 publications

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“…Interestingly, in contrast to previous studies showing an inhibitory role for SOCS3 in Th17 differentiation (35)(36)(37), a recent study by Kleinsteuber et al (38) found that overexpression of SOCS3 in human memory T cells promotes IL-17 production. A possible explanation for this discrepancy is that the role of SOCS3 is different in Th17 polarization versus activation of memory T cells that may be precommitted to a Th17 phenotype.…”

Section: Discussioncontrasting

confidence: 43%

A Negative Feedback Loop Mediated by STAT3 Limits Human Th17 Responses

Purvis

Anderson

Young

et al. 2014

The Journal of Immunology

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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+CD45RO+ T cells at a high density (HiD) or a low density (LoD) in the presence of the pro-Th17 cytokines IL-1β, IL-23, and TGF-β, 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.

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Section: Discussioncontrasting

confidence: 43%

A Negative Feedback Loop Mediated by STAT3 Limits Human Th17 Responses

Purvis

Anderson

Young

et al. 2014

The Journal of Immunology

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“…IL-17, IL-23, and IL-1␤ promote production of IL-6, IL-21, and transforming growth factor beta (TGF-␤) (35,52), the key differentiation factors for Th17 cells (7,43,48,63). For these reasons, we thought it was important to determine the source of this early IL-17 production and the conditions that prompted it.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-23-Mediated Inflammation in Pseudomonas aeruginosa Pulmonary Infection

et al. 2012

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Pseudomonas aeruginosa is an opportunistic pathogen that is capable of causing acute and chronic pulmonary infection in the immunocompromised host. In the case of cystic fibrosis (CF), chronic P. aeruginosa infection causes increased mortality by promoting overly exuberant airway inflammation and cumulative lung damage. Identifying the key regulators of this inflammation may lead to the development of new therapies that improve P. aeruginosa-related mortality. We report here that interleukin-23 (IL-23), the cytokine most clearly tied to IL-17-mediated inflammation, also promotes IL-17-independent inflammation during P. aeruginosa pulmonary infection. During the early innate immune response, prior to IL-17 induction, IL-23 acts synergistically with IL-1␤ to promote early neutrophil (polymorphonuclear leukocyte [PMN]) recruitment. However, at later time points, IL-23 also promoted IL-17 production by lung ␥␦ T cells, which was greatly augmented in the presence of IL-1␤. These studies show that IL-23 controls two independent phases of neutrophil recruitment in response to P. aeruginosa infection: early PMN emigration that is IL-17 independent and later PMN emigration regulated by IL-17. Pseudomonas aeruginosa pulmonary infection occurs in immunocompromised hosts and is associated with significant morbidity and mortality. The pathogen induces a robust neutrophil response that causes significant airway damage and does not always eliminate the pathogen. In cystic fibrosis (CF), where infection is chronic, the inflammation causes cumulative airway damage that is a major contributor to morbidity and mortality (41,46,62). Identifying the immune mediators that promote this inflammation is the first step in developing new therapies that can improve outcomes in chronic P. aeruginosa pulmonary infection.We and others have previously shown that airway interleukin-23 (IL-23) and IL-17 levels correlate with infection status and inflammation in individuals with CF (12,15,38) and that lymphocytes from CF-derived draining lymph nodes produce higher levels of IL-17 than non-CF disease controls (3). We have also shown that both IL-23 and IL-17 are critical for neutrophil recruitment in a murine model of chronic P. aeruginosa pulmonary infection (14). While these data demonstrate that the IL-23/ IL-17 proinflammatory axis is active during P. aeruginosa airway infection and in CF, the studies did not isolate the actions of IL-23 from those of IL-17.Historically, IL-17 has been credited with promoting both neutrophil recruitment and granulopoiesis through its induction of neutrophil growth factors and chemokines, including IL-6, granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC), and macrophage inflammatory protein 2 (MIP-2) (14,24,30,38,49,54,64). IL-23, a recently identified IL-12 family member (42, 60), has been primarily characterized in the context of this Th17 response (1,25,33). Of note, however, IL-23-overexpressing mice have a hyperinflammatory phenotype and notable elevations in serum IL-1␤ and t...

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“…The TGF--mediated signal inhibits IL-6-induced SOCS3 promoter activity and prolongs STAT3 activation. 19) Activated STAT3 is known to bind IL-17A and IL17F promoter and amplifies the RORtdependent differentiation of Th17 cells. 18,20,21) All transretinoic acid (ATRA) inhibits Th17 polarization via upregulation of FoxP3, in a STAT3 independent manner.…”

Section: Discussionmentioning

confidence: 99%