Pulmonary CCR2CD4 T cells are immune regulatory and attenuate lung fibrosis development.

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 CCR2CD4 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 CCR2CD4 T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis.

Methods: Pulmonary CCR2CD4 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 CCR2CD4 T cells were increased in experimental fibrosis-specifically the CD62LCD44 effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2CD4 T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2CD4 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 CCR2CD4 T cells as compared with CCR2CD4 T cells.

Conclusion: Pulmonary CCR2CD4 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.