The goal of the current studies was to examine the early immunologic events following intranasal delivery of two different immunogens previously shown to induce selective Th2 priming in the pulmonary tract, to establish how the uptake of antigen might affect APCs and in turn influence T cell priming within the lung microenvironment. We found that a resident population of CD11cbright
cells were the principal APCs to become loaded with antigen in the lung following intranasal delivery, and that this population was phenotypically most analogous to an immature subset of dendritic cells, without an obvious segregation into either the myeloid or lymphoid lineage of dendritic cells. However, we cannot rule out the possibility that these cells represent a unique subset of airway dendritic cells or a population of incompletely committed precursor cells of monocytic origin. It is important to note that many of the previous studies examining pulmonary dendritic cells/APCs were intentionally focused on the subset of APCs expressing the highest levels of MHC class II (17
), providing a likely explanation for the apparent disparity between our phenotypic findings and those of others. However, in studies where pulmonary APCs were examined as a whole population (18
), the same phenotype as in our current studies was reported (CD11c+
MHC class IIlow
One striking aspect of our findings was the limited migration of antigen-loaded APCs from pulmonary tissues into draining lymph nodes. While Pauwels and coworkers (17
) reported migration of OVA-loaded lung APCs into draining lymph nodes, they did not examine the status of these APCs within pulmonary tissues, making it difficult to conclude the extent of emigration. However, as in our current studies, Coffman and coworkers (19
) reported the preferential retention, rather than emigration, of antigen-loaded pulmonary APCs within tissues. Interestingly, the presence of IL-10 has recently been demonstrated to impair the trafficking of antigen-loaded dendritic cells in vivo (20
), which fits well with our findings of a rapid upregulation in IL-10 expression by pulmonary tissue APCs after antigen uptake in situ. The relatively limited migration of antigen-loaded APCs into draining lymph nodes in response to intranasally delivered antigens led us to question the importance of such migration to the successful induction of T cell priming within the lung microenvironment. We found that the absence of lung-draining lymph nodes did not decrease the ability of mice to become primed via the airways, suggesting a more important role for antigen/APC/T cell interactions within local tissues. This is in marked contrast to the findings showing a defect in priming in lymph node–deficient mice following immunization via other routes of antigen delivery (12
) (Figure a). Our findings resemble those recently reported for another mucosal tissue, the intestinal tract, where gut-associated lymphoid tissue rather than secondary lymphoid organs was shown to be the primary site for T cell priming following oral delivery of immunogens (21
). Thus, T cell priming within the pulmonary tract may be more dependent on localized lymphoid organs, such as bronchus-associated lymphoid tissue, or tertiary lymphoid organs that are known to form within tissues following the initiation of certain types of inflammatory responses (22
). Both of these alternative lymphoid organs would provide a means whereby a mucosal surface, such as the pulmonary tract, is able to localize the majority of its immunologic responses, thereby minimizing the potential of repeated systemic sensitization to inhaled exogenous immunogens. However, the exact location of the initial T cell/APC interactions within the pulmonary tract in the absence of classical secondary lymphoid organs remains to be established.
Of major significance is the observation that pulmonary tissue APCs preferentially expressed Th2-promoting cytokines, including IL-10 and IL-6, within a few hours of antigen uptake. These findings provide evidence for the potential of the lung microenvironment to favor the generation of Th2-dominated immune responses. Indeed, while the codelivery of LPS promoted the expression of IL-12 by antigen-loaded APCs, levels of IL-10 and IL-6 expression were virtually unchanged and a major switch to Th1-type responses was not observed. Taken together, these data support the idea that a bias in the generation of Th2 responses is likely to predominate within this mucosal site, and that Th1-type immunity will only be induced in response to very specific types of immunogens, including live bacteria (e.g., Streptococcus
) and viruses (e.g., influenza). This idea fits well with the recent findings of several groups showing that a failure to signal strongly via toll-like receptors on APCs is associated with a default Th2 outcome (23
). Thus, APCs within the pulmonary tract may have a significantly greater threshold of activation through toll-like receptors than do APCs in other tissues, providing an explanation for their apparent major default to Th2 types of differentiation.