Science and Research

Pulmonary CCR2(+)CD4(+) 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 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.

  • Milger, K.
  • Yu, Y.
  • Brudy, E.
  • Irmler, M.
  • Skapenko, A.
  • Mayinger, M.
  • Lehmann, M.
  • Beckers, J.
  • Reichenberger, F.
  • Behr, J.
  • Eickelberg, O.
  • Konigshoff, M.
  • Krauss-Etschmann, S.

Keywords

  • Animals
  • Biomarkers/metabolism
  • Bronchoalveolar Lavage Fluid/immunology
  • CD4-Positive T-Lymphocytes/*immunology
  • Disease Models, Animal
  • Female
  • Humans
  • Lung Diseases, Interstitial/diagnosis/*immunology
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Predictive Value of Tests
  • Receptors, CCR2/*immunology
  • Sensitivity and Specificity
  • Severity of Illness Index
  • T-Lymphocytes, Regulatory/*immunology
  • *CCR2+CD4 T Cell
  • *ipf
  • *immunosuppressive
  • *pulmonary fibrosis
  • (Cooperation in Science and Technology) Action BM1201 'Developmental Origins of
  • Chronic Lung Disease'. Other authors have no competing interests to declare.
Publication details
DOI: 10.1136/thoraxjnl-2016-208423
Journal: Thorax
Pages: 1007-1020 
Number: 11
Work Type: Original
Location: ARCN, CPC-M
Disease Area: DPLD
Partner / Member: FZB, HMGU, KUM, LMU
Access-Number: 28780502
See publication on PubMed

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