Abstract:CD4+CD25+FoxP3+ regulatory T cells are decreased in patients infected with HIV and have been shown to be critical in mediating Ag tolerance in the lung. Because a subset of Pneumocystis-infected individuals develop substantial lung injury, which can be modeled in immune reconstituted scid mice, we used mouse models of Pneumocystis carinii to investigate the role of regulatory T cells in opportunistic infection and immune reconstitution. In this study, we show that CD4+CD25+FoxP3+ cells are part of the host res… Show more
“…25,26 Compared with WT mice, ␥␦ KO mice had significantly reduced levels of CXCL1, G-CSF, IL-6, and CXCL10 in BAL fluid ( Figure 3C). Of the four cytokines/chemokines observed to be significantly different, CXCL10 was the only one still elevated by 14 days.…”
Section: Tcrmentioning
confidence: 99%
“…25,26 Bleomycin USP (Hospira Pharmaceuticals Lake Forest, IL) was administered (2-U/kg body weight) in sterile PBS (100 L). Adenovirus encoding CXCL10 or green fluorescent protein (adenovirus control) was administered in 100 L of sterile saline at a concentration of 10 8 plaque-forming units.…”
Section: Oropharyngeal Administration Of Bleomycinmentioning
␥␦ T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ␥␦ T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ␦ chain of the ␥␦ T-cell receptor (␥␦ knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ␥␦ KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ␥␦ KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ␥␦ T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ␥␦ T cells produced substantial quantities of all four of these cytokines, suggesting that ␥␦ T cells are a predominant source of these proteins. To demonstrate that ␥␦ T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ␥␦ T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ␥␦ KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ␥␦ KO mice. Finally, adoptive transfer of ␥␦ T cells from CXCL10 ؊/؊ mice failed to reverse the severe fibrosis in ␥␦ KO mice. These results indicate that ␥␦ T cells promote the resolution of fibrosis through the production of
“…25,26 Compared with WT mice, ␥␦ KO mice had significantly reduced levels of CXCL1, G-CSF, IL-6, and CXCL10 in BAL fluid ( Figure 3C). Of the four cytokines/chemokines observed to be significantly different, CXCL10 was the only one still elevated by 14 days.…”
Section: Tcrmentioning
confidence: 99%
“…25,26 Bleomycin USP (Hospira Pharmaceuticals Lake Forest, IL) was administered (2-U/kg body weight) in sterile PBS (100 L). Adenovirus encoding CXCL10 or green fluorescent protein (adenovirus control) was administered in 100 L of sterile saline at a concentration of 10 8 plaque-forming units.…”
Section: Oropharyngeal Administration Of Bleomycinmentioning
␥␦ T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ␥␦ T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ␦ chain of the ␥␦ T-cell receptor (␥␦ knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ␥␦ KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ␥␦ KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ␥␦ T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ␥␦ T cells produced substantial quantities of all four of these cytokines, suggesting that ␥␦ T cells are a predominant source of these proteins. To demonstrate that ␥␦ T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ␥␦ T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ␥␦ KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ␥␦ KO mice. Finally, adoptive transfer of ␥␦ T cells from CXCL10 ؊/؊ mice failed to reverse the severe fibrosis in ␥␦ KO mice. These results indicate that ␥␦ T cells promote the resolution of fibrosis through the production of
“…A subset of CD4 + lymphocytes described as Tregs, expressing the surface marker CD25 (IL-2 receptor α) as well as the transcription factor Forkhead box protein 3 (Foxp3), have been implicated in controlling autoreactive T cells in vivo (11). Recent reports indicate that Tregs exert suppressive effects in an increasing array of pathophysiologic events (12,13), including regulation of immune responses after burn injury in mice (14) and in chronic infections such as pulmonary aspergillosis (15) and Pneumocystis pneumonia (16), and therefore might participate as mediators in ALI or its resolution.…”
Acute lung injury (ALI) is characterized by rapid alveolar injury, inflammation, cytokine induction, and neutrophil accumulation. Although early events in the pathogenesis of ALI have been defined, the mechanisms underlying resolution are unknown. As a model of ALI, we administered intratracheal (i.t.) LPS to mice and observed peak lung injury 4 days after the challenge, with resolution by day 10. Numbers of alveolar lymphocytes increased as injury resolved. To examine the role of lymphocytes in this response, lymphocyte-deficient Rag-1 -/-and C57BL/6 WT mice were exposed to i.t. LPS. The extent of injury was similar between the groups of mice through day 4, but recovery was markedly impaired in the Rag-1 -/-mice. Adoptive transfer studies revealed that infusion of CD4 + CD25 + Foxp3 + Tregs as late as 24 hours after i.t. LPS normalized resolution in Rag-1 -/-mice. Similarly, Treg depletion in WT mice delayed recovery. Treg transfer into i.t. LPS-exposed Rag-1 -/-mice also corrected the elevated levels of alveolar proinflammatory cytokines and increased the diminished levels of alveolar TGF-β and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-β inhibition. Moreover, BAL of patients with ALI revealed dynamic changes in CD3 + CD4 + CD25 hi CD127 lo Foxp3 + cells. These results indicate that Tregs modify innate immune responses during resolution of lung injury and suggest potential targets for treating ALI, for which there are no specific therapies currently available.
“…Detailed immunization and infection procedures were described previously (27). Mice were immunized with RSV M 209-223 or M2 [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] peptide at 100 g/mouse intramuscularly. Peptides were conjugated with keyhole limpet hemocyanin (KLH) by using an Imject immunogen EDC kit (Thermo Fisher Scientific, Inc., Illinois).…”
Section: Methodsmentioning
confidence: 99%
“…However, the presence of natural regulatory CD4 T cells can have a beneficial effect on immune-mediated pathology, particularly at the site of infection. Tregs have been shown to limit pulmonary inflammation and lung injury induced by pneumocystis infection (29) and to modulate herpes simplex virus-induced inflammatory lesions of the eye (46). Natural Tregs also reduce the symptoms of West Nile virus infections in both humans and mice; Treg-deficient mice were more likely to develop lethal infection (25).…”
The role of epitope-specific regulatory CD4 T cells in modulating CD8 T-cell-mediated immunopathology during acute viral infection has not been well defined. In the murine model of respiratory syncytial virus (RSV) infection, CD8 T cells play an important role in both viral clearance and immunopathology. We have previously characterized two RSV epitope-specific CD4 T-cell responses with distinct phenotypic properties. One of them, the IA b M 209 -specific subset, constitutively expresses FoxP3 and modulates CD8 T-cell function in vitro. We show here that the IA b M 209 -specific CD4 T-cell response regulates CD8 T-cell function in vivo and is associated with diminished RSV-induced illness without affecting viral clearance at the site of infection. Achieving the optimal balance of regulatory and effector T-cell function is an important consideration for designing future vaccines.A subset of CD4 T cells with regulatory function (Treg) has been shown to play an important role in modulating adaptive immune responses. Natural Tregs are characterized by the expression of FoxP3 and participate in reducing the activation of CD8 T-cell responses in peripheral lymphoid organs (11, 20,35). This modulation can diminish the ability of adaptive immune responses to control systemic infections (4). However, the presence of natural regulatory CD4 T cells can have a beneficial effect on immune-mediated pathology, particularly at the site of infection. Tregs have been shown to limit pulmonary inflammation and lung injury induced by pneumocystis infection (29) and to modulate herpes simplex virus-induced inflammatory lesions of the eye (46). Natural Tregs also reduce the symptoms of West Nile virus infections in both humans and mice; Treg-deficient mice were more likely to develop lethal infection (25). Viral infection can also induce antigen-specific CD4 T cells that express FoxP3 (27), and their role in protective immunity and immunopathology needs more detailed investigation.T lymphocytes are key components of adaptive immunity against respiratory syncytial virus (RSV) infection. Children with T-cell deficiencies have delayed virus clearance and are more susceptible to fatal RSV infection (10, 18). The absence of T cells infiltrating into lung is associated with fatal RSV infections in children without recognized underlying disease (49). In the murine model, CD8 T cells play a major role in RSV clearance, presumably through direct cytotoxicity to infected cells and the generation of immunocompetent molecules (2, 15, 43); depletion of CD8 T cells in mice results in delayed viral clearance (14). The CD8 T-cell response also induces immunopathology in primary infection of mice (15,32,48). Transferring high doses of CD8 T cells facilitates virus clearance but also causes hemorrhagic pneumonia and enhanced disease (6, 14). These studies demonstrate that while CD8 T cells are required for viral clearance, they are responsible for immunopathology. We have described the pattern of CD8 T-cell responses that occur in mice that are the F 1...
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