The role of CCR2 + CD4 + T cells in lung fibrosis

INTRODUCTION: T cells have been suggested to play important roles in the development of lung fibrosis. C-C Chemokine receptor 2 (CCR2), the receptor of macrophage chemoattractant protein-1, is expressed by many immune cell types including T cells.The broad inhibition of CCR2-dependent signaling was shown to attenuate the development of experimental lung fibrosis. However, the role of CCR2 + CD4 + T cells in lung fibrosis is unknown. 2.OBJECTIVES: To investigate the phenotype and function of CCR2 + CD4 + T cells using the bleomycin-induced lung fibrosis model and BALF samples from adult patients with lung fibrosis. 3.RESULTS: After bleomycin instillation mice were analysed every 3 rd day by FACS: CCR2 + CD4 + T cells in lung and BALF increased during the fibrosis progress, peaking at day 12 after bleomycin instillation. Therefore, pulmonary CCR2 + and CCR2 - CD4 + T cells were sorted at day 12 by FACS for transcriptomic profiling. This revealed the most upregulated transcription factor and cytokine were FoxP3 and IL-10, suggesting a regulatory phenotype. A suppressor assay showed that CCR2 + but not CCR2 - CD4 + T cells, inhibited the proliferation of T effector cells. Adoptive transfer of CCR2 + CD4 + T cells at day 2 after bleomycin, led to reduced inflammation and fibrosis at day 12. In BAL samples from human IPF patients, CCR2 + CD4 + T cells were increased compared to controls and showed a higher expression of Treg markers FoxP3 and CD25 than CCR2 - CD4 + T cells. 4.CONCLUSION: Pulmonary CCR2 + CD4 + T cells increased in experimental lung fibrosis and have an immunosuppressive function. During the early phase, CCR2 + CD4 + T cells have a protective effect on fibrosis development. A similar phenotype of CCR2 + CD4 + T cells was found in BALF of IPF patients.