Pulmonary CCR2+CD4+ T cells are immune regulatory and attenuate lung fibrosis development

Abstract

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.

Keywords: CCR2+CD4 T Cell; IPF; immunosuppressive; pulmonary fibrosis.