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CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung

Abstract

Allergic asthma is a T helper type 2 (TH2)-dominated disease of the lung. In people with asthma, a fraction of CD4+ T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression is increased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here we found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4+ T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT TH2 cells. We found that CX3CR1 signaling promoted TH2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient TH2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for TH1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.

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Figure 1: Airway disease in CX3CR1-deficient mice.
Figure 2: AHR, airway inflammation and cytokine response in mice treated with CX3CR1 blocking reagents.
Figure 3: Airway disease in T cell–injected mice.
Figure 4: Number and phenotype of CX3CR1-expressing CD4+ T cells.
Figure 5: Frequency and phenotype of injected TH2 cells.
Figure 6: T cell proliferation and apoptosis.

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Acknowledgements

We thank N. Guy, V. Thieffin and A. Barbot for animal care, J. Cazareth and F. Larbret for cell sorting and S. Kirschnek (Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich) for providing the MIG-mBcl-2 and MIGR1 vectors. IFN-γ–specific antibody R4-6A2 and IL-4–specific antibody 11B11 were kind gifts from DNAX Research Institute. Cx3cr1GFP/GFP mice were a gift from S. Jung (Weizmann Institute of Science, Immunology Department). This research was supported by the Fondation pour la Recherche Medical, the Agence Nationale de la Recherche, the French Society of Allergology, the French Pneumologie Society, the Genavie foundation and the Pays de la Loire and Provence Alpes Cote d'Azur regional councils.

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C.M. and V.B. conducted most of the experiments and contributed to data analysis. A.K., S.F. and D.D. measured lung resistance and compliance and performed lung histology. V.M. provided technical help. D.L., M.L., Y.L. and A.M. performed experiments with HDM. E.H. and R.C. contributed to early experiments aimed at monitoring chemokine receptor expression in lung T cells. N.G. and V.J. wrote the manuscript. V.J. conceived of and directed the project.

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Correspondence to Valerie Julia.

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The authors declare no competing financial interests.

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Mionnet, C., Buatois, V., Kanda, A. et al. CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nat Med 16, 1305–1312 (2010). https://doi.org/10.1038/nm.2253

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