CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses

Varona, Rosa; Villares, Ricardo; Carramolino, Laura; Goya, Íñigo; Zaballos, Ángel; Gutiérrez, Julio; Torres, Miguel; Martı́nez-A, Carlos; Márquez, Gabriel

doi:10.1172/jci11297

Cited by 203 publications

(219 citation statements)

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“…Two recent studies of CCR6-deficient mice confirmed this, and showed CCR6/CCL20 involvement in the control of leukocyte homeostasis in the gut [30,31]. In CCR6-deficient mice, CD11b + CD11c + myeloid DC are clearly decreased in the subepithelial dome of PP, since these cells are displaced mainly to the interfollicular region [30,31].…”

Section: P=000377; Two-tailed T-testmentioning

confidence: 75%

“…3). We and others showed that CCR6-deficient mice have increased numbers of TCR § g T cells within the small intestinal mucosa [30,31]. A real-time quantitative reverse transcription (RT)-PCR estimation of mRNA levels in mouse colonic mucosa revealed that basal CD8 transcript levels were six-to eightfold higher in CCR6-deficient mice than in the WT group.…”

Section: Ccr6-deficient Mice Are Protected Against Dss-induced Colitismentioning

confidence: 95%

Section: P=000377; Two-tailed T-testmentioning

confidence: 99%

“…In CCR6-deficient mice, CD11b + CD11c + myeloid DC are clearly decreased in the subepithelial dome of PP, since these cells are displaced mainly to the interfollicular region [30,31]. CCR6-deficient mice also have increased numbers of T cell subpopulations within the intestinal mucosa [30,31]. These alterations in gut leukocyte homeostasis have functional consequences, as indicated by the diminished humoral response of CCR6-deficient mice to orally administered antigen and their decreased IgA response to an enteric pathogen such as rotavirus [30].…”

Section: P=000377; Two-tailed T-testmentioning

confidence: 99%

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CCR6 has a non‐redundant role in the development of inflammatory bowel disease

et al. 2003

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Antigen-loaded tissues such as the intestinal mucosa must simultaneously elicit appropriate immune response to innocuous bacteria and food proteins, and to potentially harmful antigens. Impairment of the mechanisms controlling this response may mediate the excessive immune reaction that can lead to tissue destruction and inflammatory intestinal diseases, including inflammatory bowel disease. The intestinal epithelium influences local immune responses through the expression of adhesion molecules, costimulatory factors, cytokines and chemokines. CCL20, a g -chemokine expressed in epithelia from colon and other intestinal tissue, plays a role in immune responses of intestinal mucosa, as deduced from the defects in intestinal leukocyte homeostasis shown by mice lacking CCR6, the CCL20 receptor. We studied the response of CCR6-deficient mice in two models of inflammatory bowel disease. The data show that absence of CCR6 resulted in less severe intestinal pathology in animals treated with dextran sodium sulfate. Conversely, CCR6 deficiency alters leukocyte homeostasis and the cytokine environment in the intestinal mucosa; these changes are sufficient to confer susceptibility to trinitrobenzene sulfonic acid-induced intestinal inflammation in the otherwise resistant C57BL/6J mouse strain. These results suggest that the CCR6/ CCL20 axis has a critical, non-redundant role in the in vivo control of immune responses in the intestine.

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Section: P=000377; Two-tailed T-testmentioning

confidence: 75%

Section: Ccr6-deficient Mice Are Protected Against Dss-induced Colitismentioning

confidence: 95%

Section: P=000377; Two-tailed T-testmentioning

confidence: 99%

Section: P=000377; Two-tailed T-testmentioning

confidence: 99%

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CCR6 has a non‐redundant role in the development of inflammatory bowel disease

et al. 2003

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“…C57BL/6 mice were originally purchased from the Jackson Laboratory. CCR6 À/À mice were generated in our laboratory [30] and backcrossed for nine generations onto the C57BL/6 background. The C57BL/6-Tg (ACTB-EGFP)1Osb strain was kindly provided by Dr. Masaru Okabe (Osaka University, Japan).…”

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confidence: 99%

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

et al. 2009

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The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4 1 T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4 1 T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6 À/À mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3 1 cell frequency characterized CNS tissues from CCR6 À/À compared with CCR6 1/1 mice during the disease effector phase. Transfer of CCR6 1/1 Treg to CCR6 À/À mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3 1 cells and recovery of the cytokine balance in CCR6 À/À mouse CNS. Competitive assays between CCR6 1/1 and CCR6 À/À Treg adoptively transferred to CCR6 À/À mice showed impaired ability of CCR6 À/À Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4 1 Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.Key words: Chemokines . EAE/MS . Inflammation . T cells Introduction EAE is a CNS disease characterized by mononuclear cell infiltration and demyelination; it is used to study certain aspects of human MS. EAE can be induced via immunization with neural antigens such as myelin oligodendrocyte glycoprotein (MOG). The immunopathological event in EAE and MS initiates when autoreactive T cells in the systemic immune compartment are activated and cross the blood-brain barrier [1]. Re-encounter of encephalitogenic T cells with their antigen leads to reactivation and expansion of autoreactive T cells, which in turn stimulate microglia/astrocyte activity, with increased release of proinflammatory cytokines and chemokines. The action of these mediators leads to demyelination and axon degeneration [2,3]. After antigen contact, naive CD4 1 T cells differentiate into various effector-cell subsets characterized by the cytokines they produce and by their immune regulatory functions. Th1 and Th17 cytokine profile effector cells and antigen-specific Treg have a critical role in EAE pathogenesis [4][5][6][7][8][9][10]. In MOG-induced EAE, both antigen-specific T-effector and Treg differentiate and proliferate in the periphery before migrating to the CNS [9]. Differentiation is accompanied by sequential expression of selectins, integrins, and chemokine receptors responsible for T-cell-subset recruitment to and extravasation at inflammation sites. The correct in vivo location of these cell subsets, necessary for their interaction with accessory or target cells, is regulated by [11], which are assumed to have a critical impact on MS and EAE pathogenesis [12]. St...

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Chemokine and Cytokine Modulators

Fuentes

Mirzadegan

Wilhelm

2003

Burger's Medicinal Chemistry and Drug Discovery

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The ability to respond to exogenous stimuli is a key characteristic in the survival of multicellular organisms. Both chemokines and cytokines participate in this process with different mechanisms. Chemokines are mostly involved in chemoattraction of different cell types to inflamed tissues. Cytokines, on the other hand, regulate gene expression in a wide variety of cell types. Both types of molecules are mostly inducible, although some participate in homeostatic processes. Chemokines exert their action through the activation of seven‐transmembrane spanning receptors also called G‐protein‐coupled receptors. Cytokine receptors are usually formed of two or more single‐spanning membrane subunits and phosphorylation is crucial in the signaling cascade. Because of the nature of the receptors, significant information is available regarding attempts to block chemokine receptors with small molecule antagonists. The situation is quite different for cytokine receptors, in which most of the antagonists described so far are either receptor antibodies or soluble receptors. In this chapter we summarize data available for both families.

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CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses

Cited by 203 publications

References 38 publications

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues

Chemokine and Cytokine Modulators

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CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses

Cited by 203 publications

References 38 publications

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

Chemokine and Cytokine Modulators

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CCR6 regulates EAE pathogenesis by controlling regulatory CD4⁺ T‐cell recruitment to target tissues