Background Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2+CD4+ T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2+ cell populations might either increase or decrease disease pathogenesis depending on their subtype.
Objective To investigate the role of CCR2+CD4+ T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis.
Methods Pulmonary CCR2+CD4+ T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments.
Results Frequencies of CCR2+CD4+ T cells were increased in experimental fibrosis—specifically the CD62L-CD44+ effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2+CD4+ T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2+CD4+ T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3+ CD25+ cells within bronchoalveolar lavage fluid CCR2+CD4+ T cells as compared with CCR2-CD4+ T cells.
Conclusion Pulmonary CCR2+CD4+ T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease.
- pulmonary fibrosis
- CCR2+CD4 T Cell
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Contributors Acquisition of data: KM, YY, EB, MI, AS, MM and ML; conception, design, supervision: SK-E; analysis and interpretation: SK-E, KM, YY, EB, JB, MI, OE, MK; recruitment of patients and human sample collection: FR and JüB; wrote manuscript: SKE, KM and YY; approved and edited manuscript: OE, MK, JüB, FR, MI, JB, ML, AS, EB and MM.
Funding This work was supported by the German ResearchFoundation (1973 4-1).
Competing interests KM, MK, OE and SK-E are partners of the European COST (Cooperation in Science and Technology) Action BM1201 ‘Developmental Origins of Chronic Lung Disease’. Other authors have no competing interests to declare.
Ethics approval Institutional review board, University of Munich.
Provenance and peer review Not commissioned; externally peer reviewed.
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