Absence of CCR8 Does Not Impair the Response to Ovalbumin-Induced Allergic Airway Disease

Goya, Íñigo; Villares, Ricardo; Zaballos, Ángel; Gutiérrez, Julio; Kremer, Leonor; Gonzalo, José-Ángel; Varona, Rosa; Carramolino, Laura; Serrano, Antonio; Pallarés, Pilar; Criado, Luis M.; Kolbeck, Roland; Torres, Miguel; Coyle, Anthony J.; Gutierrez-Ramos, José-Carlos; Martı́nez-A, Carlos; Márquez, Gabriel

doi:10.4049/jimmunol.170.4.2138

Cited by 86 publications

(67 citation statements)

References 48 publications

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“…The role for CCR8 in mediating Th2 cell recruitment also remains controversial. Although Chensue et al (47) initially described defective Th2 cell migration in mice deficient in CCR8, studies by other groups, including ourselves (27,37), have suggested that CCR8 does not contribute to the allergic response. However, based on our hypothesis that mast cell-derived CCL1 mediates lung inflammation through a CD4 ϩ T lymphocytedependent mechanism, we re-evaluated the role of CCR8 in mast cell-driven mucosal inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…This discrepancy is based to some extent on in vivo experimental model systems using different Ags and/or adjuvants. Immunization and challenge with low-dose soluble Ag primes for a mast cell-dependent inflammatory response, whereas high-dose Ag in adjuvant immunization results in a T lymphocyte-dependent mucosal inflammatory response independent of mast cells (8,27,37). To understand the role of mast cells and CCL1 in vivo, we next used a mast cell-dependent system (8) and measured CCL1 mRNA in the lung tissue of wt and mast cell-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

“…CCR8-deficient mice were generated as described (27). The mouse model of lung inflammation used here consists of a sensitization phase (OVA, 10 g/200 l PBS/mouse i.p.…”

Section: Mice and In Vivo Proceduresmentioning

confidence: 99%

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Coordinated Involvement of Mast Cells and T Cells in Allergic Mucosal Inflammation: Critical Role of the CC Chemokine Ligand 1:CCR8 Axis

Gonzalo

Qiu

Lora

et al. 2007

The Journal of Immunology

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CCL1 is the predominant chemokine secreted from IgE-activated human and mouse mast cells in vitro, colocalizes to mast cells in lung biopsies, and is elevated in asthmatic airways. CCR8, the receptor for CCL1, is expressed by ∼70% of CD4+ T lymphocytes recruited to the asthmatic airways, and the number of CCR8-expressing cells is increased 3-fold in the airways of asthmatic subjects compared with normal volunteers. In vivo, CCL1 expression in the lung is reduced in mast cell-deficient mice after aeroallergen provocation. Neutralization of CCL1 or CCR8 deficiency results in reduced mucosal lung inflammation, airway hyperresponsiveness, and mucus hypersecretion to a similar degree as detected in mast cell-deficient mice. Adenoviral delivery of CCL1 to the lungs of mast cell-deficient mice restores airway hyperresponsiveness, lung inflammation, and mucus hypersecretion to the degree observed in wild-type mice. The consequences of CCR8 deficiency, including a marked reduction in Th2 cytokine levels, are comparable with those observed by depletion of CD4+ T lymphocytes. Thus, mast cell-derived CCL1- and CCR8-expressing CD4+ effector T lymphocytes play an essential role in orchestrating lung mucosal inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Coordinated Involvement of Mast Cells and T Cells in Allergic Mucosal Inflammation: Critical Role of the CC Chemokine Ligand 1:CCR8 Axis

Gonzalo

Qiu

Lora

et al. 2007

The Journal of Immunology

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“…CCL1 is expressed in the thymus and CCR8/ CCL1 interactions may play a role in T REG cell development by either directing the localization of these cells to specific thymic structures or by rescuing them from negative selection upon TCR/ MHC activation given that CCR8 signaling has been shown to have antiapoptotic effects (59 -62). However, it should be noted that CCR8-deficient mice do not exhibit any of the characteristics of the severe autoimmune and lymphoproliferative disorder resulting from FOXP3 deficiency (63,64). Therefore, either the role of CCR8 in T REG development and function is not essential or chemokine receptor redundancy (e.g., CCR4) compensates for the absence of CCR8 function.…”

Section: Cd4mentioning

confidence: 99%

CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes

Soler

Chapman

Poisson

et al. 2006

The Journal of Immunology

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129

109

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CD4+ Th2 cells are important regulators of allergic inflammation. CCR8 is thought to play a role in Th2-mediated responses, however, expression of CCR8 in peripheral blood has not been fully characterized. Using a fluorescent form of the ligand selective for CCR8 (F-CCL1), we identified the leukocytes expressing CCR8 in human, monkey, and mouse peripheral blood. CCR8 expression is primarily restricted to a subset of human CD4 memory T lymphocytes (15%). Approximately 40% of CCR8+CD4+ T cells express Th2 cytokines IL-4 or IL-13 while 13% express the Th1 cytokine IFN-γ. In fact, 50% of all Th2, but only 5% of Th1, cells express CCR8. Upon anti-CD3/anti-CD28 mAb-mediated activation, CCR8+CD4+ T cells secrete 3- to 7-fold higher levels of IL-4, IL-5, IL-9, and IL-13 and 10- to 20-fold lower levels of IFN-γ or IL-17, compared with CCR8−CD4+ memory T cells. Two-thirds of CCR8+CD4 T cells express cutaneous lymphocyte-associated Ag while the majority lack gut-homing receptors. CCR8+CD4+ cells express CCR7 and CD62L and are present in spleen and lymph nodes of mice. Approximately 25% of CCR8+CD4 T cells express CD25high while 20% of CCR8+CD4+ express the T regulatory cell transcription factor FOXP3 accounting for 60% of all FOXP3-expressing CD4+ T cells. In conclusion, CCR8 marks a diverse subset of CD4 memory T cells enriched for T regulatory and Th2 cells which have the potential for recruitment into sites of allergic inflammation where they could participate in the induction and regulation of the allergic response.

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“…CCR8, the receptor for the ␤-chemokine CCL1 (7)(8)(9), is expressed in Th2-polarized T cells (10,11) and has been implicated in allergic inflammation (12), although whether CCR8 has a critical role in asthma remains controversial (13)(14)(15). CCR8 also has a potential role in atherogenesis (16), can act as human immunodeficiency virus coreceptor (17), and is a target for certain virally encoded chemokines (18).…”

mentioning

confidence: 99%

Analysis of Post-translational CCR8 Modifications and Their Influence on Receptor Activity

Gutiérrez

Kremer

Zaballos

et al. 2004

Journal of Biological Chemistry

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Post-translational modifications of the extracellular portions of receptors located in the cell membrane can contribute to modulating their biological activity. Using a mutagenesis approach in which single or multiple Tyrto-Phe, Thr-to-Ala, Ser-to-Ala, and Asn-to-Gln substitutions were made at the appropriate positions, we analyzed the sulfation and glycosylation state of the murine CCR8 chemokine receptor, and the way in which these post-translational modifications affect CCR8 activity. A Y14Y15-to-F14F15 CCR8 mutant was less sulfated than the wild-type receptor. An N8-to-Q8 mutant was less glycosylated than wild-type, and a double T10T12-to-A10A12 mutant showed even less glycosylation. We established a flow cytometric analysis with an Fc-fused form of mouse CCL1 to determine precisely the ligandbinding activity of these mutants. Single mutants at amino acid positions 8, 10 or 12 bound CCL1-Fc similarly to wild-type CCR8, whereas the F14F15 double mutant was essentially inactive and the A10A12 double mutant showed about 65% of wild-type ligand-binding activity. Calcium flux activity assays were performed with these mutants, yielding results consistent with those from the ligand binding assays. These data indicate that sulfation at specific positions of the N-terminal domain of mouse CCR8 is critical for its biological activity, whereas glycosylation has a minor influence.

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Absence of CCR8 Does Not Impair the Response to Ovalbumin-Induced Allergic Airway Disease

Cited by 86 publications

References 48 publications

Coordinated Involvement of Mast Cells and T Cells in Allergic Mucosal Inflammation: Critical Role of the CC Chemokine Ligand 1:CCR8 Axis

Coordinated Involvement of Mast Cells and T Cells in Allergic Mucosal Inflammation: Critical Role of the CC Chemokine Ligand 1:CCR8 Axis

CCR8 Expression Identifies CD4 Memory T Cells Enriched for FOXP3+ Regulatory and Th2 Effector Lymphocytes

Analysis of Post-translational CCR8 Modifications and Their Influence on Receptor Activity

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