Molecular Mechanisms in Allergy and Clinical Immunology
Pulmonary T cells and eosinophils: Coconspirators or independent triggers of allergic respiratory pathology?,☆☆,

https://doi.org/10.1067/mai.2001.116002Get rights and content

Abstract

Etiologic discussions of allergic respiratory pathology frequently engender rabid constituencies of pro-T cell or proeosinophil disciples, each claiming, often with religious fervor, the importance of their leukocyte. However, increasing evidence suggests that the exclusionary rhetoric from either camp is inadequate to explain many of the pathologic changes occurring in the lung. Data from both asthmatic patient and mouse models of allergic respiratory inflammation suggest that, in addition to cell-autonomous activities, T-cell and eosinophil interactions may be critical to the onset and progression of pulmonary pathology. These studies also suggest that T-lymphocyte subpopulations and eosinophils communicate by means of both direct cell-cell interactions and through the secretion of inflammatory signals. Collectively, the data support an expanded view of T-cell and eosinophil activities in the lung, including both immunoregulative activities and downstream effector functions impinging directly on lung function. (J Allergy Clin Immunol 2001;107:945-57.)

Section snippets

Inflammatory mechanisms in asthma

In the majority of patients, asthma appears to be initiated by the immune system and, more specifically, occurs as a consequence of allergen-mediated pulmonary inflammation. Studies of allergic asthmatic subjects and of allergen-induced pulmonary pathology in animal models have indicated that the immune cells responsible for causing the inflammation and airway hyperresponsiveness (AHR) characteristic of asthma are most likely mast cells, lymphocytes, eosinophils, or some combination thereof.4

T cells are critical to the regulation of immune responses

The initiation and regulation of pulmonary inflammatory responses are absolutely dependent on T-lymphocyte activities. In large part they orchestrate these responses through the synthesis and release of inflammatory mediators (eg, cytokines), which results in the influx of proinflammatory leukocyte subtypes and the execution of effector functions. The character of a specific inflammatory response is associated with the particular pattern or combinations of cytokines secreted by lymphocyte

Current paradigms of eosinophil effector functions

Since the mid-1980s, a great deal of evidence has been collected, demonstrating a potential destructive, and thus pathogenic, role for eosinophils in asthma.36 Although differences in effector functions exist among mammalian orders, human eosinophils mediate effects from at least 5 independent mechanisms that allow the eosinophil to modulate the intensity of pulmonary inflammation, as well as elicit the cell death and loss of structural integrity of the lung, leading to pulmonary dysfunction.

TH2 and asthma too

Asthma and other allergic diseases have been defined as TH2-driven diseases on the basis of the distinct expression profile of cytokines from T cells recruited to the lung.58 Allergen-challenge mouse models of respiratory inflammation, specifically those models using transgenic (eg, IL-4,57 IL-5,59 IL-9,10 and IL-1360) and gene knockout (eg, IL-4,61, 62 IL-5,63 IL-9,64 IL-10,65 and IL-1362, 66 and B cell–deficient,67 αβ T cell–deficient,68, 69 and γδ T cell–deficient69, 70, 71) mice, perturbing

TH1 and TH2: Is it all that it’s thought to be?

Since the concept of TH1 versus TH2 cells first emerged, there has been little challenge to this paradigm, particularly with regard to asthma pathogenesis. In fact, inhibiting TH2 and stimulating TH1 responses has, in large part, driven therapeutic initiatives. This TH2 hypothesis of asthma pathogenesis is at best based on relative increases in TH2 cellular responses. Although convenient, this paradigm has and needs to be challenged. In different experimental systems TH1 cells provide signals

CD4+ cells

With dogmatic reverence, CD4+ T lymphocytes have been characterized as the cell type responsible for the pulmonary pathology associated with allergic airways disease. These studies have included the characterization of cells recruited to the airways in asthmatic subject28, 90 and mouse models,91 the adoptive transfer of these cells in syngeneic hosts,92, 93 and the use of neutralizing antibodies in mouse models to deplete CD4+ cells.94 More recently, the availability of gene knockout mice has

CD8+ cells

The precise contribution of CD8+ cells to the development and/or suppression of airways inflammation and AHR has been difficult to define. Several studies suggest that CD8+ cells have no role in, or even attenuate, the development of AHR and airways inflammation in asthma. Studies of CD8 knockout mice demonstrate that the inflammation and AHR characteristic of OVA sensitization and aerosol challenge is unaffected by the elimination of CD8+ cells (Table I). In particular, assessments of BAL

T cells and eosinophils: Coconspirators leading to pulmonary inflammation

Recently published studies provide evidence for a previously uncharacterized direct T cell-eosinophil interaction. In both an allergen challenge122 and a parasite infestation123 model system, effector function of murine eosinophils includes antigen presentation to T cells. The importance of these interactions are highlighted in eosinophil transfer experiments in the mouse (Fig 2).124

. Migration of eosinophils to lymph nodes and lung parenchyma suggests a functional role as antigen-presenting

Differences between asthmatic patients and mouse models of respiratory disease complicate any hypotheses explaining T-cell/eosinophil activities

Mouse studies of human disease are becoming increasingly sophisticated and allow highly reductionist dissections of the correlations between specific genes and pathologies. In particular, these models of respiratory diseases serve as valuable tools toward understanding the nature of the immune response during antigen-stimulated airways inflammation and AHR and have revealed the importance of particular pathways leading to pathology. However, important differences exist between mice and human

Eosinophils and asthma: It ain’t over until the fat granulocyte sings!

Despite studies that potentially discount the role of eosinophils or the utility of drugs that target eosinophilic inflammation, many questions remain unresolved. Asthma is a pathologic process that involves the entire bronchial tree, and as such, the importance of pathologic changes in peripheral airways related to the observed physiologic changes in airway function is critical.141 However, the distribution of the eosinophilic inflammatory infiltrate in the central and peripheral airways of

Conclusion

The lung is a dynamic site of immune cell activity, which has many consequences in health and disease. Additional study of the basic immunobiology of the lung (eg, how the pulmonary immune microenvironment of the lung is established and maintained at homeostatic baseline, as well as in disease states) will be an invaluable contribution toward understanding the development of pulmonary allergic pathologies, such as asthma. Success in future studies will likely arise through the continued use of

Acknowledgements

We thank Drs Jeffery Crosby and Huahao Shen for their contribution of unpublished data. We also thank Drs Michael Borchers and J. Paul Justice and the members of the Gelfand laboratory for many insightful debates of the issues discussed in this review. A particular note of appreciation and thanks is extended to our research program assistants, Diana Nabighian (E.W.G.) and Linda Mardel (N.A.L. and J.J.L.).

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    Supported by a grant from Merck & Co, Inc, West Point, Pa

    ☆☆

    Supported by grants from the National Institutes for Health (E.W.G.: HL-36577 and HL-61005; N.A.L. and J.J.L.: HL-58723, HL-60793, HL-65228), The Environmental Protection Agency (EWG: R825702), and the Mayo Foundation.

    Reprint requests: Nancy A. Lee, PhD, or James (Jamie) J. Lee, PhD, Mayo Clinic Scottsdale, Division of Hematology/Oncology or Pulmonary, 13400 E. Shea Blvd, Scottsdale, AZ 85259.

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