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Brudy, Eva (2014): Phenotypic characterization of CCR2+ T cells in experimental pulmonary fibrosis. Dissertation, LMU München: Medizinische Fakultät



Interstitial lung diseases (ILD) are severe chronic lung diseases characterized by an increased deposition of extracellular matrix in the lung interstitial space, leading to a thickening of the alveolar walls and impairment of the gas exchange. One of the most common entities in this category is idiopathic pulmonary fibrosis (IPF) with a mean survival time of 2 to 3 years from diagnosis. Until now, there is no curative therapy available and the symptomatic anti- inflammatory treatment and oxygen supplementation cannot prevent the development of the end stage pulmonary fibrosis. The chemokine receptor CCR2 is important for leukocyte recruitment to inflamed tissues through interaction with CCL2 (MCP-1). The blockade of the CCR2/CCL2 pathway attenuated the development of pulmonary fibrosis in mouse models. However, CCR2+ T-lymphocytes acquired regulatory functions in experimental arthritis during the course of disease. Therefore, it is unknown whether CCR2+ T cells are involved in the pathogenesis of IPF or, on the contrary, represent an unsuccessful effort of the immune system to limit the disease. Observations in paediatric patients with different forms of ILDs suggested a role for CCR2+ T cells in pulmonary fibrosis. To characterize these T cells, flow cytometric studies were performed using the bleomycin mouse model of pulmonary fibrosis. The kinetic of CCR2+ T cells in BALF, lung tissue, and spleen following intratracheal administration of bleomycin (BLM) was assessed at time points between day 3 and day 21. To determine, if the constellation of naïve, central memory and effector memory T cells changes after BLM treatment, and to which of these subtypes CCR2+ T cells belong to, the cells were additionally stained for CD62L and CD44. For further characterization of CCR2+ T cells, chemokine receptor co-expression with CCR2 was investigated at the time point of the maximal presence of CCR2+ T cells. Total T cell numbers increased in BAL and lung tissue but not in spleen. Percentages of CD62LlowCD44hi effector memory T cells increased in lung tissue in the early phase of BLM induced fibrosis, while the CD62LhiCD44low naïve T cell population decreased. The percentage of CCR2+ T cells increased following BLM treatment with a maximum on day 12. The majority of CCR2+CD4+ T cells showed a Tem phenotype. CCR3, CCR4, CCR6, CXCR4, and CXCR5 expressing cells increased within the pulmonary CD4+ T cell population following bleomycin treatment. Among CD8+ T cells from treated mice, CCR5, CCR6, and CXCR5 positive cells were increased. CCR7 was highly co-expressed with CCR2 in saline and bleomycin treated mice, whereas co-expression of CCR3, CCR4, CCR6 and CXCR5 increased significantly in treated mice. The results indicate an activation of pulmonary T cell populations following bleomycin treatment. CCR2+CD4+ T cells probably take part on this T cell response as they exhibit an effector memory phenotype and increase following BLM treatment. In contrast, the stable percentages of the different T cell subtypes in spleens gave no hint for a systemic T cell reaction. The pattern of chemokine receptor expression argues against a Th1 polarization and towards a Th2, Th17 or TFH polarization of CCR2+ T cells.