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

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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.

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