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

Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie und Krauss-Etschmann, Susanne (2017): Pulmonary CCR2(+)CD4(+) T cells are immune regulatory and attenuate lung fibrosis development. In: Thorax, Bd. 72, Nr. 11: S. 1007-1020

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0040-6376
• Allianz-/Nationallizenz: Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
• Sprache: Englisch