IL‐9 is a Th17‐derived cytokine that limits pathogenic activity in organ‐specific autoimmune disease

Stephens, Geoffrey L.; Swerdlow, Bonnie; Benjamin, Emelia J.; Coyle, Anthony J.; Humbles, Alison A.; Kolbeck, Roland; Fung, Michael

doi:10.1002/eji.201040879

Cited by 49 publications

(32 citation statements)

References 52 publications

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“…The expression level of IL-9 is further enhanced under Th9 differentiation conditions compared with CD4 ϩ T cell blasts, which suggests a possibility that NFAT1 may cooperate with Th9 lineage-determining transcription factors as well. IL-9 has also newly been described as a Th17 type cytokine, and subsequent roles of IL-9 in Th17-mediated inflammatory responses have also been implicated (18,76). Interestingly, the HTLV-transformed cell line Hut-102 has an IL-9-producing Th17 phenotype.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Factor of Activated T Cells 1 (NFAT1)-induced Permissive Chromatin Modification Facilitates Nuclear Factor-κB (NF-κB)-mediated Interleukin-9 (IL-9) Transactivation

Jash

Sahoo

Kim

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Nuclear Factor of Activated T Cells 1 (NFAT1)-induced Permissive Chromatin Modification Facilitates Nuclear Factor-κB (NF-κB)-mediated Interleukin-9 (IL-9) Transactivation

Jash

Sahoo

Kim

et al. 2012

Journal of Biological Chemistry

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“…IL-9 is also produced by Th17 cells (25,26). We examined the role of Smad2/3 and IRF4 under Th17 conditions.…”

Section: Smad2 and Smad3 Physically Interact With Irf4mentioning

confidence: 99%

Smad2/3 and IRF4 Play a Cooperative Role in IL-9–Producing T Cell Induction

Tamiya

Ichiyama

Kotani

et al. 2013

The Journal of Immunology

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IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-β in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell–specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-β signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-β stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-β enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells.

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“…Th9 and IL-9 cells are pro-inflammatory, and appear to function in a broad spectrum of autoimmune diseases and allergic inflammation (16,17,24,25). On the other hand, IL-9 has also been reported to promote the maintenance of tolerant environment by enhancing both Tregs and mast cell-mediated immunosuppressive functions (26)(27)(28), and by limiting the pathogenic activity of Th17 (29). In addition, IL-9 may lead to decreased production of IL-12 and limit the capacity of APCs to induce a Th1-type immune response (30).…”

Section: Introductionmentioning

confidence: 99%

Th9 cells promote antitumor immune responses in vivo

Lu¹,

Hong²,

Li³

et al. 2012

J. Clin. Invest.

294

322

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Th9 cells are a subset of CD4 + Th cells that produce the pleiotropic cytokine IL-9. IL-9/Th9 can function as both positive and negative regulators of immune response, but the role of IL-9/Th9 in tumor immunity is unknown. We examined the role of IL-9/Th9 in a model of pulmonary melanoma in mice. Lack of IL-9 enhanced tumor growth, while tumor-specific Th9 cell treatment promoted stronger antitumor responses in both prophylactic and therapeutic models. Th9 cells also elicited strong host antitumor CD8 + CTL responses by promoting Ccl20/Ccr6-dependent recruitment of DCs to the tumor tissues. Subsequent tumor antigen delivery to the draining LN resulted in CD8 + T cell priming. In agreement with this model, Ccr6 deficiency abrogated the Th9 cell-mediated antitumor response. Our data suggest a distinct role for tumor-specific Th9 cells in provoking CD8 + CTL-mediated antitumor immunity and indicate that Th9 cell-based cancer immunotherapy may be a promising therapeutic approach.

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IL‐9 is a Th17‐derived cytokine that limits pathogenic activity in organ‐specific autoimmune disease

Cited by 49 publications

References 52 publications

Nuclear Factor of Activated T Cells 1 (NFAT1)-induced Permissive Chromatin Modification Facilitates Nuclear Factor-κB (NF-κB)-mediated Interleukin-9 (IL-9) Transactivation

Nuclear Factor of Activated T Cells 1 (NFAT1)-induced Permissive Chromatin Modification Facilitates Nuclear Factor-κB (NF-κB)-mediated Interleukin-9 (IL-9) Transactivation

Smad2/3 and IRF4 Play a Cooperative Role in IL-9–Producing T Cell Induction

Th9 cells promote antitumor immune responses in vivo

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