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Section of Pulmonary and Critical Care Yale University School of Medicine New Haven, CT 06520
In sensitized animals that are repeatedly exposed to inhaled Ag, airway inflammation wanes over time. This regulatory effect has been observed for many years in different species, and it limits the development of chronic airway disease (1, 2, 3, 4, 5, 6). We speculate that this type of regulatory pathway may also limit airway inflammation in healthy humans. To specifically define the components necessary for this regulatory effect, we developed a model that allows us to eliminate host T cell responses, yet still stimulate Th-induced inflammation using adoptively transferred, in vitro-generated Th cells. Thus, using RAG–/– hosts, we showed we can induce T cell inhibition (1). These studies convincingly demonstrate that immune regulation induced by repeated exposure to inhaled Ag during inflammation is not regulatory T cell (Treg) mediated. We are encouraged to see that our data are supported by Van Hove’s study (5), showing that Treg numbers inversely correlate with inhibition of inflammation. In our model, we avoid the use of the term "tolerance" since this effect is not mediated by T cells, and we call it "airway inflammation-related inhibition of disease (AIRID)."
Our model tests for inhibition of effector Th responses, whereas Van Hove et al. and others (3, 5, 7) use models that test for inhibition of primary immune responses. Thus, at present, we must be cautious not to assume we are studying the same pathway of inhibition. That aside, many features of these models are similar, including the Ag-nonspecific inhibitory effect.
Comparable to findings of Van Hove et al., our studies also revealed differences in activation markers on lung dendritic cells (DCs) from mice with acute inflammation compared with mice with inhibition of disease (our unpublished data). In AIRID, we suspect that these effects result from reduced inflammation in the lung environment, rather than being a cause of reduced inflammation. After repeated inhaled Ag exposure, we test for inhibition by challenging mice with adoptively transferred, recently in vitro-activated effector Th cells. In this system, inhaled Ag is only required for Th recruitment, not for Th proliferation. We expect that Ag-APC-T cell interactions required to provide signals for recruitment are fairly promiscuous, compared with the stringent signals required for naive T cell activation. The fairly subtle alterations in DC activation markers we have observed are unlikely to block Th cell recruitment to the lung. If recruitment was blocked, we might expect to observe Th cells elsewhere in the body, which we did not. More likely, the reduction in activation markers on lung DCs results from the marked diminution in lung inflammation.
We show that AIRID is associated with a population of TGF-
1+ macrophages. We hypothesize that repeated exposure to inhaled Ag during inflammation activates a population of suppressive macrophages that directly and potently inhibits Th cells. Studies that are ongoing in the laboratory support this hypothesis.
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