Alveolar Type II Epithelial Cells Present Antigen to CD4<sup>+</sup>T Cells and Induce Foxp3<sup>+</sup>Regulatory T Cells

Gereke, Marcus; Buer, Jan; Bruder, Dunja

doi:10.1164/rccm.200804-592oc

Cited by 97 publications

(106 citation statements)

References 60 publications

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“…However, in contrast to the results obtained for CD8 + T cell-mediated intestinal inflammation (40) or CD4 + T lymphocyte-related pulmonary disease (41), lung-specific CD8 + T cells do not differentiate into Foxp3 + Tregs nor do they become anergic, as they proliferate massively upon antigenic stimulation in vitro. Notably, when the autoreactive lymphocytes infiltrating the lung are CD4 + T cells (23,41,42), their fate, function, and phenotype are quite opposite those we observed for CD8 + T cells.…”

Section: Discussioncontrasting

confidence: 82%

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Tosiek

Gruber

Bader

et al. 2011

The Journal of Immunology

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Every person harbors a population of potentially self-reactive lymphocytes controlled by tightly balanced tolerance mechanisms. Failures in this balance evoke immune activation and autoimmunity. In this study, we investigated the contribution of self-reactive CD8+ T lymphocytes to chronic pulmonary inflammation and a possible role for naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that despite pulmonary inflammation, lung-specific CD8+ T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8+ T cells in the inflamed lung and lung-draining lymph nodes downregulated the expression of effector molecules, those located in the spleen appeared to be partly Ag-experienced and displayed a memory-like phenotype. Because ex vivo-reisolated self-reactive CD8+ T cells were very well capable of responding to the Ag in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8+ T cells in the lung. Notably, CD8+ T cell tolerance established in the lung depends only partially on the function of nTregs, because self-reactive CD8+ T cells underwent only biased activation and did not acquire effector function after nTreg depletion. However, although transient ablation of nTregs did not expand the population of self-reactive CD8+ T cells or exacerbate the disease, it provoked rapid accumulation of activated CD103+CD62Llo Tregs in bronchial lymph nodes, a finding suggesting an adaptive phenotypic switch in the nTreg population that acts in concert with other yet-undefined mechanisms to prevent the detrimental activation of self-reactive CD8+ T cells.

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Section: Discussioncontrasting

confidence: 82%

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Tosiek

Gruber

Bader

et al. 2011

The Journal of Immunology

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“…For example, crosstalk between Tregs and the intestinal or retinal epithelium is an important determinant of both immune tolerance and Treg proliferation (40)(41)(42). Type II alveolar epithelial cells (AECs) can present antigen to naive Tcells through the Class II major histocompatibility complex (MHC), and induce the proliferation of Tregs, in part through a transforming growth factor (TGF)-b-dependent mechanism (43). In the context of our model, Tregs might down-regulate AEC CXCL12 expression in a contact-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

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Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

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“…Furthermore, we could show that AECII display self-antigens through major histocompatibility complex class-II molecules which results in the functional activation of auto reactive CD4 + T cells. At the same time AECII maintain lung tolerance by secreting factors promoting the induction of Foxp3+ regulatory T cells 4 .…”

Section: Discussionmentioning

confidence: 99%

“…AECII have been shown to participate in cytokine production in inflamed airways and to even act as antigenpresenting cells in both infection and T-cell mediated autoimmunity [1][2][3][4][5][6][7][8] . Therefore, they are especially interesting also in clinical contexts such as airway hyper-reactivity to foreign and self-antigens as well as infections that directly or indirectly target AECII.…”

Section: Introductionmentioning

confidence: 99%

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Flow Cytometric Isolation of Primary Murine Type II Alveolar Epithelial Cells for Functional and Molecular Studies

Gereke

Autengruber

Gröbe

et al. 2012

JoVE

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Throughout the last years, the contribution of alveolar type II epithelial cells (AECII) to various aspects of immune regulation in the lung has been increasingly recognized. AECII have been shown to participate in cytokine production in inflamed airways and to even act as antigenpresenting cells in both infection and T-cell mediated autoimmunity [1][2][3][4][5][6][7][8] . Therefore, they are especially interesting also in clinical contexts such as airway hyper-reactivity to foreign and self-antigens as well as infections that directly or indirectly target AECII. However, our understanding of the detailed immunologic functions served by alveolar type II epithelial cells in the healthy lung as well as in inflammation remains fragmentary. Many studies regarding AECII function are performed using mouse or human alveolar epithelial cell lines [9][10][11][12] . Working with cell lines certainly offers a range of benefits, such as the availability of large numbers of cells for extensive analyses. However, we believe the use of primary murine AECII allows a better understanding of the role of this cell type in complex processes like infection or autoimmune inflammation. Primary murine AECII can be isolated directly from animals suffering from such respiratory conditions, meaning they have been subject to all additional extrinsic factors playing a role in the analyzed setting. As an example, viable AECII can be isolated from mice intranasally infected with influenza A virus, which primarily targets these cells for replication 13 . Importantly, through ex vivo infection of AECII isolated from healthy mice, studies of the cellular responses mounted upon infection can be further extended.Our protocol for the isolation of primary murine AECII is based on enzymatic digestion of the mouse lung followed by labeling of the resulting cell suspension with antibodies specific for CD11c, CD11b, F4/80, CD19, CD45 and CD16/CD32. Granular AECII are then identified as the unlabeled and sideward scatter high (SSC high ) cell population and are separated by fluorescence activated cell sorting 3 .In comparison to alternative methods of isolating primary epithelial cells from mouse lungs, our protocol for flow cytometric isolation of AECII by negative selection yields untouched, highly viable and pure AECII in relatively short time. Additionally, and in contrast to conventional methods of isolation by panning and depletion of lymphocytes via binding of antibody-coupled magnetic beads 14,15 , flow cytometric cell-sorting allows discrimination by means of cell size and granularity. Given that instrumentation for flow cytometric cell sorting is available, the described procedure can be applied at relatively low costs. Next to standard antibodies and enzymes for lung disintegration, no additional reagents such as magnetic beads are required. The isolated cells are suitable for a wide range of functional and molecular studies, which include in vitro culture and T-cell stimulation assays as well as transcriptome, proteome or secretome ...

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Alveolar Type II Epithelial Cells Present Antigen to CD4⁺T Cells and Induce Foxp3⁺Regulatory T Cells

Cited by 97 publications

References 60 publications

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Flow Cytometric Isolation of Primary Murine Type II Alveolar Epithelial Cells for Functional and Molecular Studies

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Alveolar Type II Epithelial Cells Present Antigen to CD4+T Cells and Induce Foxp3+Regulatory T Cells

Cited by 97 publications

References 60 publications

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Flow Cytometric Isolation of Primary Murine Type II Alveolar Epithelial Cells for Functional and Molecular Studies

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Alveolar Type II Epithelial Cells Present Antigen to CD4⁺T Cells and Induce Foxp3⁺Regulatory T Cells