© 2004 American Thoracic Society
Who Is Captain of the Inflammatory Ship in Asthma?University of Wisconsin Medical School Madison, Wisconsin Airway inflammation is a characteristic feature of asthma and felt to be important in determining the persistence and severity of this disease. In the past decade, our appreciation of the complexity of the inflammatory process in asthma has expanded almost exponentially with new contributors, i.e., dendritic cells, regulatory T cells, and chemokines, added to an already expansive list of participants in these airway events. It is, however, unlikely that any of these cellular or chemical mediators act independently, and the orchestration of the process, or processes, is essential. Thus, an important question remains: Who is the "captain" of this inflammatory ship? In trying to answer this question, an important feature of asthma to consider is its chronicity. Chronicity is illustrated by asthma persistence and recurrent exacerbations of inflammation, where, for example, cells in or recruited to the lung have the ability to "recall" their sensitization for allergens and, thus, re-initiate the inflammatory response. Of the participants in the inflammatory war, the lymphocyte has the properties of long life, memory and a repertoire for many of the key inflammatory mediators.
In this issue of the Journal (pp. 587–595), Aronica and coworkers used a novel approach to investigate the contribution of Th1 and Th2 memory T cells to allergen-induced airway inflammation and hyperresponsiveness (1). Naive CD4+ T cells were isolated from the spleen and lymph nodes of DO11.10 mice carrying the transgene for a T cell receptor that recognizes an ovalbumin peptide. The naive T cells were then cultured under Th1- or Th2-polarizing conditions with ovalbumin and antigen-presenting cells from wild-type BALB/c mice. The resulting antigen-specific Th1 (interferon- Following a subsequent aerosolized ovalbumin challenge, Th2 recipient mice, that had not been previously exposed to antigen, developed post-challenge increases in airway responsiveness to methacholine identical to mice that had been actively sensitized (intraperitoneal administration of ovalbumin in alum). The Th2 recipients and actively sensitized mice also had a similar airway inflammatory response, with a characteristic increase in eosinophils both in bronchoalveolar lavage fluid and lung tissues following aerosol airway challenge. Transfer of Th1 cells did not induce increases in airway hyperresponsiveness or eosinophilic inflammation. Furthermore, and surprisingly, cotransfer of Th1 with Th2 cells neither enhanced nor reduced the recall response of Th2 memory cells. Thus, in this model, Th2 memory cells, alone, appear to determine the development of airway hyperresponsiveness and pulmonary eosinophilia to an antigen challenge, and Th1 memory cells do not modulate this response.
It was also somewhat surprising that the transferred Th2 cells had no "bystander" effect. The availability of anticlonotypic antibody to the ovalbumin T cell receptor allowed the investigators to identify antigen-specific T cells (presumably donor derived). They did not observe nonspecific expansion of interleukin-4–producing endogenous CD4+ T cells. Of interest, in Th2 recipients, there was expansion of interferon- Other investigators have established a role for "effector" Th2 cells in airway hyperresponsiveness using transfer of in vitro differentiated T cell receptor transgenic Th2 cells into naive mice; however, the cells were immediately (within 24 hours) re-exposed to antigen in vivo via inhalation challenge. Similar to Th2 memory cells, Th2 effector cells also provoked airway eosinophilia and hyperresponsiveness (2–4). Th2 cells likely contribute to airway inflammation and hyperresponsiveness through (1) the generation of interleukin-4, which is critical for Th2 differentiation; (2) interleukin-5, a key factor for eosinophil maturation and egress from the bone marrow; and (3) interleukin-13, a cytokine that contributes to mucus hypersecretion, induces airway smooth muscle hyperresponsiveness, and activates airway stromal cells to produce chemokines such as eotaxin.
The contribution of Th1 cells to antigen-induced airway inflammation and hyperresponsiveness has been more controversial and possibly complex. Th1 cells, through their generation of interferon- Collectively, adoptive transfer studies have confirmed a role for Th2 cells in antigen-induced airway hyperresponsiveness and suggest that the contribution of Th1 may depend on the conditions and timing of antigen exposure. What these studies do not tell us is whether ex vivo priming and polarization of Th1 and Th2 cells is equivalent to that induced in vivo. Activation and polarization of T cells in the presence of airway dendritic cell is probably very different from in vitro models. Finally, the majority of the adoptive transfer studies have been performed in BALB/c mice, which are genetically more susceptible for the induction of Th2-mediated immune responses. The contribution and interaction of Th1 and Th2 in other mouse strains would be helpful. The studies by Aronica and colleagues (1) have caused us to rethink some of our current paradigms in which the consequences of allergic inflammation are influenced by a cytokine balance or imbalance and now shift our focus toward identifying the conditions under which Th2 memory cells can be regulated, and from this information begin to answer the question: Who is the "captain" of the inflammatory reaction and under what conditions does this leadership exist? FOOTNOTES Conflict of Interest Statement: E.A.B.K. has no declared conflict of interest; W.W.B. has no declared conflict of interest. REFERENCES
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–producing) or Th2 (interleukin4–producing) cells were adoptively transferred into naive wild-type BALB/c recipients. A key, and novel, component of their study was that the in vitro sensitized cells were "parked" in vivo for 24 days in the absence of antigen exposure to allow them to convert from an activated effector phenotype (high expression of CD25 and CD69) to a quiescent "memory" phenotype (low expression of CD25 and CD69, high expression of CD44).