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Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development.
Thorax 72, 1007-1020 (2017)
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Ccr2+cd4 T Cell ; Ipf ; Immunosuppressive ; Pulmonary Fibrosis; Fibrocyte Recruitment; Mice; Disease; Injury; Ccr2; Interleukin-10; Macrophages; Mcp-1/ccr2; Expression; Tolerance