Distinct Chemokine Receptor Axes Regulate Th9 Cell Trafficking to Allergic and Autoimmune Inflammatory Sites

Kara, Elodie; Comerford, Iain; Bastow, Cameron R.; Fenix, Kevin; Litchfield, W. Reid; Handel, Tracy M.; McColl, Shaun R.

doi:10.4049/jimmunol.1203089

Cited by 54 publications

(39 citation statements)

References 52 publications

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“…In mouse models of asthma (in which HDM, Aspergillus and ovalbumin (OVA) are used as sensitizers), T H 9 cells are detectable in the respiratory tract and draining lymph nodes, particularly during early stages of the disease 47, 53, 54 . In the OVA sensitization model, T H 9 cells are a principal in vivo source of IL-9 during allergic airway disease as determined by an IL-9 fate reporter mouse 55 .…”

Section: Th9 Cells In Immunity and Diseasementioning

confidence: 99%

“…EAE is associated with T H 1 and T H 17 cell responses, and T H 17 cells have been identified in the central nervous system (CNS) of patients with multiple sclerosis 78 . T H 9 cells are present in the draining lymph nodes and CNS of mice administered myelin proteolipid protein (PLP) 180-199 peptide to induce EAE 53 , and the adoptive transfer of myelin oligodendrocyte glycoprotein (MOG)-specific T cells cultured under T H 9 cell-inducing conditions into RAG-deficient mice promoted EAE disease 23, 30, 79 . Although T H 9 cell-mediated EAE is not as severe as the EAE disease induced by T H 17 cells 79 , adoptive transfer of T H 9 cells can trigger peripheral neuropathy that is not as apparent in recipients of T H 1 or T H 17 cells 7, 79 .…”

Section: Th9 Cells In Immunity and Diseasementioning

confidence: 99%

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The development and in vivo function of T helper 9 cells

2015

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The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the 20th anniversary of the first descriptions of cytokine signals that act to differentiate interleukin-9 (IL-9)-secreting T cells, this review focuses on the extracellular signals and transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease and propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.

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Section: Th9 Cells In Immunity and Diseasementioning

confidence: 99%

Section: Th9 Cells In Immunity and Diseasementioning

confidence: 99%

The development and in vivo function of T helper 9 cells

2015

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“…Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11,12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Cd4mentioning

confidence: 99%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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CD4؉ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na ؉ /H ؉ exchanger 1 (NHE1; gene name Slc9␣1)) is critically important for regulating intracellular pH (pH i ), cell volume, migration, and cell survival. The pH i influences cytokine secretion, activities of membrane-associated enzymes, ion transport, and other effector signaling molecules such as ATP and Ca 2؉ levels. However, whether NHE1 regulates Th9 cell development or IL-9 secretion has not yet been defined. The present study explored the role of NHE1 in Th9 cell development and function. Th cell subsets were characterized by flow cytometry and pH i was measured using 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) dye. NHE1 functional activity was estimated from the rate of realkalinization following an ammonium pulse. Surprisingly, in Th9 cells pH i and NHE1 activity were significantly higher than in all other Th cell subsets (Th1/Th2/Th17 and induced regulatory T cells (iTregs)). NHE1 transcript levels and protein abundance were significantly higher in Th9 cells than in other Th cell subsets. Inhibition of NHE1 by siRNA-NHE1 or with cariporide in Th9 cells down-regulated IL-9 and ATP production. NHE1 activity, Th9 cell development, and IL-9 production were further blunted by pharmacological inhibition of protein kinase Akt1/Akt2. Our findings reveal that Akt1/Akt2 control of NHE1 could be an important physiological regulator of Th9 cell differentiation, IL-9 secretion, and ATP production. CD4ϩ T cells participate in the regulation of the immune response during infections, autoimmunity, and cancer. CD4 ϩ T cells are an important and essential arm of the adaptive immune system (1). CD4 ϩ T cells can be divided into various subtypes based upon their cytokine secretion: T helper 1 (Th1) 4 cells produce IFN-␥ (1, 2), Th2 cells produce IL-4, IL-5, and IL-13 (3), Th17 cells produce IL-17 (4 -6), Th9 cells produce IL-9 (7-9), and suppressive regulatory T cells (Tregs) produce TGF-␤ and IL-10 (10). A great deal of experimental effort has been dedicated to decipher the development and function of various Th cell subsets. However, Th9 cell development and function remain incompletely understood.Th9 cells are a recently characterized Th cell subset recognized by their potent production of IL-9. Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11, 12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7, 13-23). The development and function of Th9 cells are regulated ...

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“…CCL20 is associated with the migration of Langerhans cells [29] , B cells [30,31] , Th17 [32,33] and type 9 helper T (Th9) cells [34] to inflammatory sites. However, the pathophysiological effects of CCL20 in severe ACD patients remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Chemokines and a CD4-Positive T Cell Subset in the Development of Conjunctival Secondary Lymphoid Follicles in an Atopic Keratoconjunctivitis Mouse Model

Shoji

Nakanishi

Ishimori

et al. 2015

Int Arch Allergy Immunol

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Background: Massive B cell lymphoid hyperplasia and its associated factors may play a role in exacerbating inflammation in allergic disorders. We here investigated the chemokines and CD4-positive T cell subset involved in the development of secondary lymphoid follicles (iCALT) in conjunctival tissues in an atopic keratoconjunctivitis mouse model (AKC mouse). Methods: NC/Nga mice were divided into three groups: AKC (percutaneous sensitization and instillation of crude house dust mite antigen), AD (percutaneous sensitization only) and C (untreated control). Pathological changes in the conjunctival tissues of each group were investigated using histological and immunohistochemical detection of CD4 and CD20. Furthermore, tissue sections of iCALT (AKC-iCALT subgroup) and conjunctiva without iCALT (AKC-conjunctiva subgroup) were obtained from AKC mice using laser-assisted microdissection. mRNA expression of chemokine and T cell subset-related transcription factors were compared between the AKC-iCALT and AKC-conjunctiva subgroups using polymerase chain reaction (PCR) array and real-time reverse transcription-PCR (RT-PCR) methods. Results: iCALT with central aggregation of CD20-positive B cells and CD4-positive T cell infiltration surrounding B cells was observed in the palpebral conjunctival tissue of the AKC group, but not in that of the AD and C groups. Chemokine and T cell subset-related transcription factor expression was confirmed using real-time RT-PCR, with significant increases in Ccl5, Ccl17, Cxl20, Cxcl3, Ccr7, Foxp3 and T-bet mRNA expression in the AKC-iCALT subgroup compared with those in the AKC-conjunctiva subgroup. Conclusions: We concluded that CCL5, CCL17 and CCL20, as well as T-bet- and Foxp3-positive lymphocytes may be iCALT-related factors and that iCALT-related chemokines are worth evaluating as biomarkers.

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Distinct Chemokine Receptor Axes Regulate Th9 Cell Trafficking to Allergic and Autoimmune Inflammatory Sites

Cited by 54 publications

References 52 publications

The development and in vivo function of T helper 9 cells

The development and in vivo function of T helper 9 cells

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Involvement of Chemokines and a CD4-Positive T Cell Subset in the Development of Conjunctival Secondary Lymphoid Follicles in an Atopic Keratoconjunctivitis Mouse Model

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