PERSPECTIVE
The Macroimportance of the Pulmonary Immune Microenvironment

Nancy A. Lee and James J. Lee

Department of Biochemistry and Molecular Biology, Samuel C. Johnson Medical Research Building, Mayo Clinic Scottsdale, Scottsdale, Arizona

The incidence of asthma is at near-epidemic levels among the peoples of industrialized countries (see review by Cookson and colleagues [1]). Hypotheses for this proliferation have included increases in air pollution, early exposure to trigger antigens (e.g., dust mites, cockroaches), genetic factors, and differences in the amount of time spent inside versus outside. Respiratory infections early in life (e.g., respiratory syncytial virus [RSV], rhinovirus, and parainfluenza) have also been proposed as predisposing factors toward the later development of asthma (see Reference 2). In contrast, infections with organisms that induce a predominant T helper (Th)1 response (e.g., tuberculosis) have been hypothesized to provide a protective effect with regard to developing the Th2-driven syndromes of asthma and allergies (3). Despite intense study of patient populations, the unique circumstances that dictate why one person's immune responses lead to asthma when others do not are still obscure.

Since 1796, when Jenner showed that inoculation with cow pox conferred protection on the recipients, theories have been proffered to explain the immune response when an organism is confronted with an antigen. At the cellular level, distinct and alterable immune responses are attributed to a number of factors, including variations in the types of responding cells, the scope and intensity of the antigen encounter, and differences in the manner of antigen presentation (see References 4 and 5). Furthermore, the cointroduction of antigen with an adjuvant is critical in determining the immune response obtained. In animal models of respiratory disease, a redundant and confounding factor has been the variability of responses obtained by even slight modifications of antigen-exposure protocols.

Recent data from mouse models of allergic respiratory inflammation, however, implicate the history of antigen exposures as another critical variable in determining the type and magnitude of an immune response. A defining example is provided by the experiments of Erb and colleagues (6) who demonstrated that prior administration of the bovine Mycobacterium tuberculosis vaccine (bacillus Calmette-Guérin [BCG]) leads to the attenuation of the Th2 reactions generally associated with a subsequent ovalbumin (OVA) intranasal challenge. In contrast, animals with no previous exposure to BCG develop, as expected, a dramatic Th2 response to an OVA challenge. A prominent hypothesis to explain these results is that the prior immune history of an organism can change the cytokine milieu of a particular tissue or organ (in this case the lung), or that subpopulations of immune cells, such as T cells, have undergone a biased differentiation in view of prior antigen exposures and cytokine production (7, 8). In particular, the expression of interleukin (IL)-4 and interferon (IFN)- has been especially scrutinized because of these cytokines' ability to promote the differentiation of Th2 cells or dramatically suppress Th2 responses, respectively (Table 1).

At first glance, the proposal that the history of antigen exposures affects ongoing responses may seem like a logical extension of early theories of acquired immunity and immune memory. However, these previously mentioned studies extend the earlier theories by suggesting that immunologic memory is not confined to exposure to identical antigens. The significant extrapolation of this concept is that the immune response to the administration of a new "second" antigen may be dependent on previous exposure to any other antigens that have been encountered in the past. The regulation of these history-dependent responses at a cellular and/or molecular level could be accomplished in several ways. For example, antigen exposure leads to cellular responses that result in the generation of memory-effector T cells localized within particular tissues or lymphoid organs (Figure 1). The presence of these memory-effector cells in discrete lymphoid tissues has been recognized for some time, including the importance of their distinct functional capabilities and capacity to synthesize certain cytokines (9). The novelty suggested by recent reports is that the presence of particular cytokines in secondary lymphoid tissues alone may influence the type of response generated by irrelevantand heretofore unseenantigens. One explanation for this phenomenon at the cellular/molecular level is that a prior exposure to antigen causes specific cell populations to secrete particular cytokines that drive either Th1 (IL-12, IL-18, IFN-) or Th2 responses (IL-4, IL-5, IL-13) (see Table 1). The presence of these polarizing cytokines may influence responses to subsequent antigen provocations, even if the subsequent antigens are not related to the first. The sources of these pulmonary cytokines may include a number of cell types in addition to memory-effector T cells, such as mast cells (12), epithelial cells of the lung (13), -T cells (16), natural killer cells (47), and macrophages (17, 18). Even eosinophils, which are known to produce IL-4 and IL-5 (19), and may also produce IL-12 after selective cytokine treatment (20), can contribute to the lung cytokine milieu. Thus, the pulmonary microenvironment may be defined by the presence of local effector cells or the cytokine milieu they create.

View larger version (42K): [in this window] [in a new window]   Figure 1.   Immune response of the pulmonary environment.

Two reports presented by Stämpfli and colleagues (21, 22) underscore the importance of the pulmonary cytokine microenvironment. In the first study (21), the authors express granulocyte macrophage-colony stimulating factor (GM-CSF) in the lung via an adenoviral construct. Both uninfected and infected mice are minimally exposed to an OVA aerosol using a protocol specifically designed not to produce signs of airway inflammation. However, in the presence of adenoviral-mediated GM-CSF expression, the mice developed classic markers of allergic respiratory inflammation in response to OVA, including pulmonary eosinophilia and goblet-cell hyperplasia. This airway inflammation was dependent on both IL-5, which is essential for the augmentation of eosinophil populations, and major histocompatibility complex (MHC) Class II, which is required for antigen presentation. GM-CSF is known to enhance eosinophil survival, but may also act as an "adjuvant" by increasing the immunogenicity of certain antigens (23, 24). The adjuvant function of GM-CSF may be caused, in part, by the synergistic effect of this cytokine with IL-4 to expand dendritic cell populations necessary for efficient antigen presentation (25). Thus, Stämpfli and associates speculated that the role of GM-CSF in promoting OVA-induced airway inflammation may be due to increased effectiveness of antigen presentation to T cells. In addition, the results of Stämpfli and coworkers imply that antigen-specific memory T cells are generated upon initial antigen exposure only in the presence of GM-CSF.

In a related study presented in this issue of the Journal (22), Stämpfli and colleagues show that IL-12, which polarizes T cells towards a Th1 phenotype, can also modulate the immune response to OVA. These investigators use a second adenoviral construct to express IL-12 concurrently with expression of GM-CSF. Interestingly, coexpression of IL-12 mitigates, but does not eliminate, the development of airway inflammation in response to OVA. Notably, the expression of IL-4 and IL-5 is decreased by 80 and 95%, respectively, and airway eosinophils are not detected. The authors conclude that the cytokine microenvironment can influence the development of a Th1- or Th2-type response. They further suggest that the nature of immunologic memory established is dependent upon whether the initial antigen exposure occurs in the presence of GM-CSF, IL-12, or both cytokines. Importantly, this study shows that the presence of a particular cytokine (in this case, IL-12) can dramatically affect the outcome of antigen provocation. There is no reason a priori to assume that this effect is limited to IL-12; other cytokines that affect the differentiation of T cells toward either a Th1 or Th2 phenotype may also influence the type and magnitude of immune responses associated with future antigen provocations (see studies examining the effects of IL-4 and IL-13 on the differentiation of Th2 cells [26, 27] and IL-4 induction of IL-5 expression by viral-specific T cells [28]). In addition to affecting T-cell differentiation, the cytokine microenvironment may also direct the specific recruitment of T-cell subsets to the lung (29, 30). The significance of each of these studies with regard to the experiments described by Stämpfli and associates is that an initial antigen exposure or viral infection could potentially generate either a Th1- or Th2-like cytokine microenvironment, which in turn may conduce or bias any subsequent immune responses.

Studies using transgenic mice constitutively expressing cytokines in specific organs/tissues also support the hypothesis that localized expression can profoundly affect the type and/or magnitude of an immune-mediated response. Two well documented examples present mice expressing the Th2 cytokines IL-4 (31, 32) or IL-5 using multiple tissue-specific promoters. In the case of IL-5, our laboratories have created mice constitutively expressing this cytokine from T cells (33), keratinocytes (J. Lee and N. Lee, unpublished observations), and the lung epithelium (34). Although mice from each transgenic line express IL-5 at a similar level (as determined by serum cytokine levels), only IL-5 expression in the lung results in pulmonary pathologies. We drew the conclusion from these studies that IL-5 effector functions were more than endocrine-mediated systemic effects on hematopoietic compartments, and probably include paracrine effector functions that are specifically executed in the local microenvironment. These studies demonstrate that localized IL-5 expression affects the type of pathology observed in the transgenic animals and can be correlated with changes in particular subpopulations of immune effector cells. However, there is a lack of evidence linking prior antigen exposure or viral infection with persistent alterations in the cytokine microenvironment that would be significant enough to either amplify or attenuate future immune responses.

The role of viral infection and the development of asthma has, in particular, been the focus of a great deal of attention. This relationship has led to speculation that antiviral host defenses change the pulmonary microenvironment. The results of Coyle and colleagues (28) and Schwarze and colleagues (35) are especially pertinent to the hypothesis that early viral infections result in persistent alterations of the cytokine microenvironment, which in turn may affect the outcome of subsequent antigen provocations. Coyle and associates showed that virus-specific CD8⁺ T cells in the lung could be induced to produce IL-5 in the presence of IL-4, demonstrating one mechanism by which T cells, produced as a consequence of an early viral infection, could lead to an exacerbation of asthma. Schwarze and associates showed that mice exposed to aerosolized OVA developed a dramatically augmented Th2 response if they had been previously exposed to RSV. Moreover, this study also demonstrated that cytokine production differed between groups of OVA-challenged animals on the basis of whether the animals had earlier experienced a RSV infection. These viral studies suggest that prior exposure to an unrelated viral antigen could result in consistent deviations in cytokine production after exposure to a second antigen. The model diagramed in Figure 2 illustrates the potential effects of two distinct and separable antigen exposures that may lead to several different outcomes based on changes within the pulmonary microenvironment. The results from murine viral infection models appear to support the hypothesis outlined in Scenario II of Figure 2; namely, that exposure to RSV leads to Th2-like persistent changes in the pulmonary cytokine microenvironment (for example, by virtue of IL-4 expression from specific subpopulations of immune effector cells). Subsequent exposure to a second unrelated antigen, such as OVA, then provokes an exaggerated Th2 response characteristic of asthma. In contrast, prior exposure to M. tuberculosis vaccine (BCG) results in a Th1-like alteration in the pulmonary cytokine milieu, and subsequent OVA provocation yields an attenuated Th2 response (6). This model also provides the most parsimonious explanation of the results from the two studies described by Stämpfli and coworkers (21, 22). The change in the pulmonary microenvironment induced by viral infection may be mimicked, in part, by ectopic expression of GM-CSF. The subsequent OVA challenge (i.e., second antigen), normally incapable of inducing an inflammatory reaction using their protocol, now produces a Th2 response. Furthermore, the concomitant expression of IL-12 (a Th1-polarizing cytokine) apparently alters the microenvironment in such a way as to attenuate this response.

View larger version (34K): [in this window] [in a new window]   Figure 2.   Antigen exposure induces microenvironmental changes that affect subsequent immune responses.

The studies outlined in this perspective appear to indicate that a logical therapeutic goal for treating asthma is to create a localized pulmonary Th1 environment. Unfortunately, systemic attempts to create a Th1 immune environment by vaccination have not yet been successful: a study examining children vaccinated for BCG found no protective effects in regard to the development of asthma (36). However, this result may indicate the necessity of creating a localized Th1 environment, highlighting the specific importance of the pulmonary microenvironment. Future studies describing the subpopulations of cells required for maintaining an appropriate cytokine milieu, as well as the precise levels of cytokines necessary to attenuate a destructive immune response, will provide much needed insight into the mechanisms by which lung homeostasis is maintained and regained after multiple viral infections and antigen provocations.

	Footnotes

Address correspondence to: Nancy A. Lee/James J. Lee, Mayo Clinic Scottsdale, SCJMRB, 13400 E. Shea Blvd., Scottsdale, AZ 85259. E-mail: nlee{at}mayo.edu or jjlee{at}mayo.edu

(Received in original form July 9, 1999).

Acknowledgments: The authors wish to acknowledge the hard work, dedication, and helpful discussions of the staff in both laboratories, whose efforts and importance have been invaluable to the authors' success and productivity. In addition, the authors wish to thank their research program assistant, Linda Mardel, without whom they could not function as an integrated group. This work was funded, in part, by the Mayo Foundation, National Institutes of Health grants HL058723 and HL60793, and the American Lung Association, Arizona Chapter.

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