Platelet-Derived Growth Factor–Producing CD4 + Foxp3 + Regulatory T Lymphocytes Promote Lung Fibrosis (original) (raw)
Related papers
Roles of T lymphocytes in pulmonary fibrosis
Journal of Leukocyte Biology, 2007
Infiltration of T lymphocytes in the lungs is common in patients with and in animal models of pulmonary fibrosis. The role of these cells in regulating the accumulation of extracellular matrix, particularly collagen, is not understood completely. Research literature provides evidence for a profibrotic, an antifibrotic, or no significant role of T lymphocytes in pulmonary fibrosis. This review offers a discussion of such evidence with the focus on phenotypes of pulmonary T lymphocytes and related profibrotic and antifibrotic mechanisms. It appears unlikely that T lymphocytic infiltration per se is the central driving force in most cases of pulmonary fibrosis. Instead, evidence suggests that T lymphocytes may modulate the inflammatory and healing responses in the lungs in a profibrotic or antifibrotic manner, depending on their phenotype. Phenotypic reshaping, rather than elimination of the infiltrating pulmonary T lymphocytes, may be a promising approach to improving outcomes in patients with pulmonary fibrosis.
American Journal of Respiratory and Critical Care Medicine, 2013
Rationale: Lymphocytes are increasingly associated with idiopathic pulmonary fibrosis (IPF). Semaphorin 7a (Sema 7a) participates in lymphocyte activation. Objectives: To define the relationship between Sema 7a and lymphocytes in IPF. Methods: We characterized the significance of Sema 7a 1 lymphocytes in humans with IPF and in a mouse model of lung fibrosis caused by lung-targeted, transgenic overexpression of TGF-b1. We determined the site of Sema 7a expression in human and murine lungs and circulation and used adoptive transfer approaches to define the relevance of lymphocytes coexpressing Sema7a and the markers CD19, CD4, or CD4 1 CD25 1 FoxP3 1 in TGF-b1-induced murine lung fibrosis. Measurements and Main Results: Subjects with IPF show expression of Sema 7a on lung CD4 1 cells and circulating CD4 1 or CD19 1 cells. Sema 7a expression is increased on CD4 1 cells and CD4 1 CD25 1 FoxP3 1 regulatory T cells, but not CD19 1 cells, in subjects with progressive IPF. Sema 7a is expressed on lymphocytes expressing CD4 but not CD19 in the lungs and spleen of TGF-b1-transgenic mice. Sema 7a expressing bone marrow-derived cells induce lung fibrosis and alter the production of T-cell mediators, including IFN-g, IL-4, IL-17A, and IL-10. These effects require CD4 but not CD19. In comparison to Sema 7a-CD4 1 CD25 1 FoxP3 1 cells, Sema7a 1 CD4 1 CD25 1 FoxP3 1 cells exhibit reduced expression of regulatory genes such as IL-10, and adoptive transfer of these cells induces fibrosis and remodeling in the TGF-b1-exposed murine lung. Conclusions: Sema 7a 1 CD4 1 CD25 1 FoxP3 1 regulatory T cells are associated with disease progression in subjects with IPF and induce fibrosis in the TGF-b1-exposed murine lung.
T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7-/- mice
Fibrogenesis & Tissue Repair, 2010
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.
The Journal of Immunology, 2006
The mechanisms by which T cells accumulate in the lungs of patients with pulmonary fibrosis are poorly understood. Because the lung is continually exposed to microbial agents from the environment, we repeatedly exposed C57BL/6 mice to the ubiquitous microorganism, Bacillus subtilis, to determine whether chronic exposure to an inhaled microorganism could lead to T cell accumulation in the lungs and subsequent pulmonary fibrosis. C57BL/6 mice repeatedly treated with B. subtilis for 4 consecutive weeks developed a 33-fold increase in the number of CD4 ؉ T cells and a 354-fold increase in ␥␦ T cells in the lung. The ␥␦ T cells consisted almost entirely of V␥6/V␦1 ؉ cells, a murine subset bearing an invariant TCR the function of which is still unknown. Treatment of C57BL/6 mice with heat-killed vs live B. subtilis resulted in a 2-fold increase in the number of CD4 ؉ T cells in the lung but no expansion of ␥␦ T cells indicating that ␥␦ cells accumulate in response to live microorganisms. In addition, mice treated with heat-killed B. subtilis developed significantly increased pulmonary fibrosis compared with mice treated with the live microorganism. Mice deficient in V␥6/V␦1 ؉ T cells when treated with B. subtilis had a 231-fold increase in lung CD4 ؉ T cells and significantly increased collagen deposition compared with wild-type C57BL/6 mice, consistent with an immunoregulatory role for the V␥6/V␦1 T cell subset. These findings indicate that chronic inhalation of B. subtilis can result in T cell accumulation in the lung and fibrosis, constituting a new model of immune-mediated pulmonary fibrosis.
The American Journal of Pathology, 2012
Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into the pathogenesis of IPF, we reanalyzed our previously published gene expression data profiling IPF lungs. Cytokine receptor-like factor 1 (CRLF1) was among the most highly up-regulated genes in IPF lungs, compared with normal controls. The protein product (CLF-1) and its partner, cardiotrophin-like cytokine (CLC), function as members of the interleukin 6 (IL-6) family of cytokines. Because of earlier work implicating IL-6 family members in IPF pathogenesis, we tested whether CLF-1 expression contributes to inflammation in experimental pulmonary fibrosis. In IPF, we detected CLF-1 expression in both type II alveolar epithelial cells and macrophages. We found that the receptor for CLF-1/CLC signaling, ciliary neurotrophic factor receptor (CNTFR), was expressed only in type II alveolar epithelial cells. Administration of CLF-1/CLC to both uninjured and bleomycin-injured mice led to the pulmonary accumulation of CD4 ؉ T cells. We also found that CLF-1/CLC administration increased inflammation but decreased pulmonary fibrosis. CLF-1/CLC leads to significantly enriched expression of T-cell-derived chemokines and cytokines, including the antifibrotic cytokine inter-feron-␥. We propose that, in IPF, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung.
Pulmonary CCR2+CD4+T cells are immune regulatory and attenuate lung fibrosis development
Thorax, 2017
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.