Contribution of CCR4 and CCR8 to antigen-specific TH2 cell trafficking in allergic pulmonary inflammation

Mikhak, Zamaneh; Fukui, Mieko; Farsidjani, Alireza; Medoff, Benjamin D.; Tager, Andrew M.; Luster, Andrew D.

doi:10.1016/j.jaci.2008.09.049

Cited by 111 publications

(99 citation statements)

References 36 publications

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“…We selected 26 Th2-specific genes that include previously reported Th2-specific genes (IL-4, IL-13, IL-5, IL-24, GATA3, CCR8, and TNFRSF8) (13,(42)(43)(44), and also new genes that were not reported previously (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

Horiuchi

Onodera

Hosokawa

et al. 2011

The Journal of Immunology

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Differentiation of naive CD4 T cells into Th2 cells is accompanied by chromatin remodeling and increased expression of a set of Th2-specific genes, including those encoding Th2 cytokines. IL-4–mediated STAT6 activation induces high levels of transcription of GATA3, a master regulator of Th2 cell differentiation, and enforced expression of GATA3 induces Th2 cytokine expression. However, it remains unclear whether the expression of other Th2-specific genes is induced directly by GATA3. A genome-wide unbiased chromatin immunoprecipitation assay coupled with massive parallel sequencing analysis revealed that GATA3 bound to 1279 genes selectively in Th2 cells, and 101 genes in both Th1 and Th2 cells. Simultaneously, we identified 26 highly Th2-specific STAT6-dependent inducible genes by DNA microarray analysis-based three-step selection processes, and among them 17 genes showed GATA3 binding. We assessed dependency on GATA3 for the transcription of these 26 Th2-specific genes, and 10 genes showed increased transcription in a GATA3-dependent manner, whereas 16 genes showed no significant responses. The transcription of the 16 GATA3-nonresponding genes was clearly increased by the introduction of an active form of STAT6, STAT6VT. Therefore, although GATA3 has been recognized as a master regulator of Th2 cell differentiation, many Th2-specific genes are not regulated by GATA3 itself, but in collaboration with STAT6.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

Horiuchi

Onodera

Hosokawa

et al. 2011

The Journal of Immunology

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“…The function of DC during allergen challenge could be the local restimulation of effector function in lung resident lymphocytes, or alternatively could be the recruitment of these effector Th2 cells [60]. In allergen-challenged mice, CD11b 1 DC are a prominent source of the chemokines CCL17 and CCL22, thus recruiting CCR4 1 Th2 cells to the lungs [3,61]. A recent study employing selective depletion of lung CD11b 1 myeloid cells (most likely CD11b 1 inflammatory DC) in CD11b-DTR mice indeed identified these cells, and not bronchial epithelial cells, as the critical source of CCL17 and CCL22 [62].…”

Section: The Role Of Lung DC Subsets In Allergy and Asthmamentioning

confidence: 99%

Origin and functional specializations of DC subsets in the lung

2010

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Lung DC bridge innate and adaptive immunity, and depending on the context, induce Th1, Th2 or Th17 response, to optimally clear infections. Conversely, lung DC can also prevent overt and harmful immune responses to harmless inhaled antigens via induction of Treg cells or via induction of neutralizing mucosal IgA antibodies. Here, we propose that these functions are not the result of a single population of DC, and instead, subsets of DC perform specialized functions.

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“…Some studies indicate a crucial role of CCR4 in the pathogenesis of asthma by recruiting Th2 cells to the site of allergen exposure (17)(18)(19). However, other studies using knockout (KO) mice for CCR4 or Abs against these chemokine receptor gathered conflicting results (19)(20)(21)(22).…”

mentioning

confidence: 99%

Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

Faustino

Fonseca

Takenaka

et al. 2013

The Journal of Immunology

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We have previously shown that regulatory T (Treg) cells that accumulate in the airways of allergic mice upregulate CC-chemokine receptor 4 (CCR4) expression. These Treg cells suppressed in vitro Th2 cell proliferation but not type 2 cytokine production. In the current study, using a well-established murine model of allergic lung disease or oral tolerance, we evaluated the in vivo activity of Treg cells in allergic airway inflammation with special focus on CCR4 function. We found that allergic, but not tolerant, mice treated with anti-CD25 Ab showed increased airway eosinophilia and IL-5– or IL-4–producing Th2 cells when compared with untreated mice. Notably, mice with CCR4 deficiency displayed an augmented airway allergic inflammation compared with wild-type or CCR2 knockout (KO) mice. The allergic phenotype of CCR4KO mice was similar to that observed in anti-CD25–treated mice. The exacerbated allergic inflammation of CCR4KO mice was directly associated with an impaired migration of Treg cells to airways and augmented frequency of pulmonary Th2 cells. Adoptive transfer of CD25+CD4+ T cells expressing high levels of CCR4, but not CCR4KO CD25+CD4+ T cells, attenuated the severe airway Th2 response of CCR4KO mice. Our results show that CCR4 is critically involved in the migration of Treg cells to allergic lungs that, in turn, attenuate airway Th2 activation and allergic eosinophilic inflammation.

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Contribution of CCR4 and CCR8 to antigen-specific TH2 cell trafficking in allergic pulmonary inflammation

Cited by 111 publications

References 36 publications

Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

Genome-Wide Analysis Reveals Unique Regulation of Transcription of Th2-Specific Genes by GATA3

Origin and functional specializations of DC subsets in the lung

Regulatory T Cells Migrate to Airways via CCR4 and Attenuate the Severity of Airway Allergic Inflammation

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