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

https://doi.org/10.1016/j.jaci.2008.09.049Get rights and content

Background

Recruitment of antigen-specific TH2 cells into the lung is critical for the development of allergic airway inflammation. Although CCR4 and CCR8 are preferentially expressed on TH2 cells and CCR4, CCR8, and CXCR3 ligands are increased in asthma, the specific relative contribution of these receptors to antigen-specific TH2 cell trafficking into the allergic lung is not known.

Objective

To determine the relative contribution of the chemokine receptors CCR4, CCR8, and CXCR3 to antigen-specific TH2 cell trafficking in a murine model of allergic pulmonary inflammation.

Methods

We used adoptive transfer experiments to compare the trafficking of wild-type antigen-specific TH2 cells with antigen-specific TH2 cells deficient in CCR4, CCR8, or CXCR3.

Results

CCR4-deficient antigen-specific TH2 cells failed to traffic efficiently into the lung and the airways. In contrast, CCR8-deficient antigen-specific TH2 cells accumulated in these sites. Trafficking of CXCR3-deficient antigen-specific TH2 cells and CCR4-deficient and CCR8-deficient antigen-specific TH1 cells were comparable to their wild-type counterparts. Approximately 60% of IL-4–producing antigen-specific T cells expressed CCR4. Disruption of CCR4-mediated antigen-specific TH2 cell trafficking decreased the levels of TH2-type cytokines in the airways and reduced airway eosinophilia and mucus production.

Conclusions

Our study demonstrates that CCR4 is required for the efficient entry of antigen-specific TH2 cells into the lung and the airways in a murine model of allergic pulmonary inflammation.

Section snippets

Mice

Thy1.1+ OTII, Thy1.2+ OTII, and CXCR3−/− mice were obtained as previously described.28 CCR8−/− mice were a gift from Sergio A. Lira (Mount Sinai School of Medicine, New York, NY).17 CCR4−/− and C57BL/6 mice were purchased from the Jackson Laboratory. All mice were in the C57BL/6 background. CCR4−/−OTII, CXCR3−/−OTII, CCR8−/−OTII, and Thy1.1+Thy1.2+ mice were bred in our laboratory. Chemokine receptor-deficient OTII mice were generated by breeding male OTII mice with female chemokine

CCR4 deficiency diminishes antigen-specific TH2 cell trafficking into the lung and the airways, whereas CXCR3 and CCR8 deficiency are not associated with a trafficking defect

To study the relative contribution of CCR4, CCR8, and CXCR3 to the trafficking of antigen-specific TH2 cells, we compared the homing of wild-type OTII TH2 cells, which are transgenic for the T-cell receptor recognizing ovalbumin peptide323-339, with the homing of OTII TH2 cells deficient in CCR4, CCR8, or CXCR3 into the lung and the airways in vivo, using a competitive adoptive transfer model.32 We chose an adoptive transfer approach to isolate the effect of deficiency in CCR4, CCR8, or CXCR3

Discussion

In this study, we have delineated the role of CCR4, CCR8, and CXCR3 in antigen-specific TH2-cell trafficking. We have shown that CCR4 deficiency decreases antigen-specific TH2-cell trafficking into the allergic lung, CXCR3 deficiency has no impact, and CCR8 deficiency leads to an accumulation of these cells. The roles of CCR4 and CCR8 were specific for antigen-specific TH2 cells because antigen-specific TH1-cell trafficking was not affected by CCR4 or CCR8 deficiency.

There are conflicting

Acknowledgments

We thank Sergio Lira (Mount Sinai, New York, NY) for the CCR8−/− mouse, Craig Gerard (Children's Hospital, Boston, Mass) for the CXCR3−/− mouse, and Daniel Campbell (Benaroya Research Institute, Seattle, Wash) for the CCL22-IgG fusion protein DNA construct.

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    Supported by the National Institutes of Health (R37-AI40618 to A.D.L. and K08AI67519 to Z.M.).

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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