T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7(-/-) mice

Background: C-C chemokine receptor (CCR) 7 is a regulator of dendritic cell and T cell migration, and its role in tissue wound healing has been investigated in various disease models. We have previously demonstrated that CCR7 and its ligand, chemokine (C-C motif) ligand (CCL) 21, modulates wound repair in pulmonary fibrosis (PF) but the mechanism of this is unknown. The objective of this study was to investigate whether the absence of CCR7 protects against bleomycin (BLM)-induced PF. CCR7(-/-) mice failed to mount a fibrotic pulmonary response as assessed by histologic collagen staining and quantification by hydroxyproline. We hypothesized that the prominent characteristics of CCR7(-/-) mice, including elevated levels of cytokine and chemokine mediators and the presence of bronchus-associated lymphoid tissue (BALT) might be relevant to the protective phenotype. Results: Pulmonary fibrosis was induced in CCR7(+/+) and CCR7(-/-) mice via a single intratracheal injection of BLM. We found that the lung cytokine/chemokine milieu associated with the absence of CCR7 correlated with an increase in BALT, and might be attributable to regulatory T cell (Treg) homeostasis and trafficking within the lungs and lymph nodes. In response to BLM challenge, CCR7(-/-) mice exhibited an early, steady increase in lung CD4(+) T cells and increased CD4+ CD25(+) FoxP3(+) Tregs in the lungs 21 days after challenge. These findings are consistent with increased lung expression of interleukin-2 and indoleamine 2,3-dioxygenase in CCR7(-/-) mice, which promote Treg expansion. Conclusions: Our study demonstrates that the protective phenotype associated with BLM-treated CCR7(-/-) mice correlates with the presence of BALT and the anchoring of Tregs in the lungs of CCR7(-/-) mice. These data provide novel evidence to support the further investigation of CCR7(-/-) mediated Treg trafficking in the modulation of BLMinduced PF.