Key Points
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Although it is firmly established that T helper 2 (TH2) cells are central to the pathogenesis of asthma, the molecular mechanisms that control TH2-cell trafficking to the lung in asthma are unknown.
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Lipid mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2) are not stored and released; instead, when cells are activated, these mediators are synthesized de novo from arachidonic acid by enzymes of the lipoxygenase and cyclooxygenase pathways respectively.
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Molecular identification of the receptors for LTB4 and PGD2 has led to the discovery that two of these receptors, BLT1 and DP2 (also known as CRTH2) are highly expressed by specific T-cell subsets and are functional on these cells.
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Classically, LTB4 has been thought to contribute to the pathogenesis of asthma through the recruitment and activation of neutrophils and eosinophils, whereas PGD2 has been thought to contribute to oedema formation, mucus production and bronchoconstriction.
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Generation of BLT1-deficient mice has revealed an unexpected role for LTB4 in T-cell trafficking early in allergic pulmonary inflammation. LTB4, which is probably produced in the airways of immunized animals following mast-cell and/or alveolar macrophage activation by aerosolized allergen, seems to be the main chemoattractant that directs effector T cells to the airways immediately after aeroallergen challenge.
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Generation of DP1-deficient mice has also revealed an unexpected role for PGD2 in T-cell trafficking early in allergic pulmonary inflammation. PGD2 is also produced in the airways following mast-cell and/or alveolar macrophage activation, and it induces expression of the chemokine CC-chemokine ligand 22 (also known as MDC), which augments TH2-cell recruitment to the airways.
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Experiments using mice that are deficient in STAT6 (signal transducer and activator of transcription 6) indicate that T-cell recruitment during the amplification and/or maintenance of allergic pulmonary inflammation is directed by peptide chemokines. Cytokines produced by TH2 cells that are recruited to the airways during the initiation phase of allergic inflammation activate resident pulmonary cells in a STAT6-dependent manner, to secrete chemokines that attract TH2 cells and eosinophils.
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We propose that eicosanoids and chemokines cooperate and have non-redundant, sequential roles in directing T cells in asthma: the initial T-cell recruitment to the airways in allergic immune responses is directed by LTB4 and PGD2, whereas the subsequent T-cell recruitment that is required to amplify and/or maintain allergic pulmonary inflammation is directed by chemokines.
Abstract
Recruitment of T cells to the airways is crucial in the pathogenesis of asthma, and it is thought to be mediated mainly by peptide chemokines. By contrast, lipid mediators such as leukotrienes and prostaglandins have classically been thought to contribute to asthma pathogenesis by other mechanisms. However, as we discuss here, the recent molecular identification of leukotriene and prostaglandin receptors, as well as the generation of mice that are genetically deficient in them, has revealed that two of these lipids — leukotriene B4 and prostaglandin D2 — also direct T-cell migration and seem to cooperate with chemokines in a non-redundant, sequential manner to recruit T cells to the airways in asthma.
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A.D.L. and A.M.T. gratefully acknowledge grant support from the National Institutes of Health, United States, and the Dana Foundation, United States.
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Glossary
- ALLERGIC PULMONARY INFLAMMATION
-
Lung inflammation induced by immediate and delayed hypersensitivity reactions to air-borne antigens. Allergic pulmonary inflammation is characterized pathologically by T helper 2 cell and eosinophil infiltration, and mucus hypersecretion, and physiologically by hyper-responsiveness to bronchoconstricting stimuli.
- ESTERIFIED
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Combination of one organic compound with another through the formation of an ester: that is, the condensation of a hydroxyl group of one compound with a carboxyl group of another.
- LIPOCALIN
-
Member of a large superfamily of small, mostly extracellular proteins of diverse function. Lipocalins have two common features: an eight-stranded antiparallel β-sheet closed back on itself to form a continuously hydrogen-bonded β-barrel; and the ability to bind small, mainly hydrophobic molecules.
- CENTRAL MEMORY T (TCM) CELLS
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Antigen-experienced CD8+ T cells that lack immediate effector function but are able to mediate rapid recall responses. They also rapidly develop the phenotype and function of effector memory cells after restimulation with antigen. Central memory T cells retain the migratory properties of naive cells and therefore circulate through the secondary lymphoid organs.
- EFFECTOR MEMORY T CELLS
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Antigen-experienced CD8+ T cells that have immediate effector capabilities, such as cytotoxicity, and can efficiently migrate to peripheral sites of inflammation.
- LEUKOCYTE ROLLING
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The initial interactions that occur between circulating leukocytes and the endothelial cells of inflamed tissues are transient low-affinity adhesive interactions that are mediated by the selectin family of adhesion molecules, resulting in the rolling of leukocytes along the endothelial surface. The process of rolling slows leukocytes to velocities less than those of circulating erythrocytes.
- LEUKOCYTE FIRM ADHESION
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The interactions of rolling leukocytes with chemokines or lipid mediators, such as leukotriene B4, at the endothelial surface lead to the activation of leukocyte integrins — another family of adhesion molecules. When activated, integrins mediate high-affinity adhesive interactions between leukocytes and endothelial cells, resulting in the arrest and firm adhesion of rolling leukocytes.
- INTRAVITAL MICROSCOPY STUDIES
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Examination of biological processes, such as leukocyte–endothelial cell interactions, in living tissue. In general, translucent tissues are used, such as the mesentery or cremaster muscle, which can be exteriorized and mounted for microscopic observation.
- BRONCHOALVEOLAR LAVAGE
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Delivery of saline to the airways and airspaces of the lungs, followed by retrieval of the fluid. This procedure is carried out to obtain samples of the cells, proteins or other materials that line the aerated regions of the lungs.
- BRONCHOCONSTRICTION
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Contraction of smooth muscle that surrounds the airways, resulting in airway narrowing and air-flow obstruction, which produces symptoms of wheezing, shortness of breath and chest tightness. In asthma, bronchoconstriction is thought to be mediated by inflammatory mediators, including prostaglandins and leukotrienes, and it can usually be reversed using β-adrenergic agonist or anticholinergic medications.
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Luster, A., Tager, A. T-cell trafficking in asthma: lipid mediators grease the way. Nat Rev Immunol 4, 711–724 (2004). https://doi.org/10.1038/nri1438
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DOI: https://doi.org/10.1038/nri1438
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