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.
- Milger, K.
- Yu, Y.
- Brudy, E.
- Irmler, M.
- Skapenko, A.
- Mayinger, M.
- Lehmann, M.
- Beckers, J.
- Reichenberger, F.
- Behr, J.
- Eickelberg, O.
- Konigshoff, M.
- Krauss-Etschmann, S.
Keywords
- Animals
- Biomarkers/metabolism
- Bronchoalveolar Lavage Fluid/immunology
- CD4-Positive T-Lymphocytes/*immunology
- Disease Models, Animal
- Female
- Humans
- Lung Diseases, Interstitial/diagnosis/*immunology
- Mice
- Mice, Inbred C57BL
- Phenotype
- Predictive Value of Tests
- Receptors, CCR2/*immunology
- Sensitivity and Specificity
- Severity of Illness Index
- T-Lymphocytes, Regulatory/*immunology
- *CCR2+CD4 T Cell
- *ipf
- *immunosuppressive
- *pulmonary fibrosis
- (Cooperation in Science and Technology) Action BM1201 'Developmental Origins of
- Chronic Lung Disease'. Other authors have no competing interests to declare.