Large populations of dendritic cells (DCs) are found throughout the respiratory tract, the most prominent comprising a contiguous network dispersed throughout the epithelium and underlying mucosa of the conducting airways. Most of the available information on these cells comes from studies on tissues from experimental animals; however, comparable networks of DCs have also been formally demonstrated in humans.1-3

These populations of DCs in the lung and airway wall are now known to play a central role in the maintenance of immunological homeostasis in the respiratory tract (reviewed by Holt and Stumbles1). As the principal resident antigen presenting cells (APC) in these tissues under steady state conditions, they serve as the local “gatekeepers” of the immune system. The principal function of these DCs is surveillance for incoming (inhaled) antigens deposited on airway mucosal surfaces, which they sample principally via receptor mediated endocytosis.4 Resident airway cells perform this function avidly but are relatively inefficient in presenting these antigens to T cells, due principally to poor surface expression of co-stimulator molecules such as CD80/CD86 which are obligatory second signals for T cell activation. Maturation of DCs from antigen acquirers into antigen presenters normally does not occur until the cells emigrate from peripheral tissues (bearing the antigens they have acquired) into the T cell zones of regional lymph nodes.5 During or immediately after this migration they mature under the influence of a variety of different cytokines including interleukin (IL)-1, tumour necrosis factor (TNF)α, and IL-4, but in particular granulocyte-macrophage colony stimulating factor (GM-CSF) which appears to serve as the “master regulator” in this process.5 This functional maturation is readily observable in vitro by culturing respiratory tract DCs in GM-CSF, which induces cycling of intracellular MHC class II complexed with bound antigenic peptide(s) from intracellular vesicles onto the cell surface, and also induces concomitant surface expression of high levels of co-stimulator molecules.4

This strict compartmentalisation of the functions of DCs is believed to play an important role in protecting delicate airway tissues from damage resulting from unwarranted local T cell activation, a process which inevitably results in release of potentially toxic cytokines. Instead, these activation events are usually restricted to lymph nodes and result in expansion of relevant clones of T memory cells which subsequently recirculate back into the airway tissues.

An increasing body of indirect evidence suggests that precocious maturation of the APC functions of DCs prior to their migration to draining lymph nodes may be an important factor in the pathogenesis of immunoinflammatory respiratory diseases such as atopic asthma. A hallmark of this disease is the presence of unusually high numbers of activated T cells in the airway mucosa,6 signifying the local presence of active APC. GM-CSF, the principal stimulant for maturation of DCs, is produced at high levels in the airway mucosa of asthmatic subjects7 and several studies in patients with asthma (reviewed by Holt and Stumbles1) report increased numbers of DCs expressing activation markers in these tissues.

Information from experimental models suggests that the DC mediated immune surveillance process is highly efficient in immunocompetent adult animals. Under steady state conditions, populations of DCs in the airway wall are renewed every 36–38 hours8 as antigen bearing DCs migrate to draining lymph nodes and are replaced by incoming immature bone marrow derived DC precursors. However, in the face of local challenge with inert antigens, allergens and, in particular, microbial pathogens, the pace of this sampling process further accelerates to maximise the efficiency of transmission of antigenic “danger” signals to the central immune system.1 The highly dynamic nature of this DC sampling process is virtually unique to the conducting airways, underscoring the central importance of the local DC network in immunological protection of these delicate tissues.

Recent studies4 indicate that, as well as regulating the overall intensity of the adaptive immune response to local antigen challenge, signals from respiratory tract DCs determine the balance which ultimately develops between the Th1 and Th2 components of immunological memory against inhaled antigens. It is now evident that the default function of resting airway DCs is to prime selectively the naive immune system for expression of Th2 polarised immunity. Furthermore, their capacity to promote alternate Th1 polarised immunity, which is required for protection against both infection and against allergic sensitisation to inhalants, relies absolutely upon their receipt of appropriate stimulatory signals from GM-CSF in conjunction with TNFα, IL-1, or CD40 ligand.

Thus, in adult animals, respiratory tract DCs appear to orchestrate both quantitative and qualitative aspects of local host immune defence. However, it is equally evident that, at least in experimental animal species, the situation is markedly different in the key period between birth and weaning. Studies principally in the rat9 ,10indicate that, at birth, DCs are present in only very small numbers in the airway wall and, moreover, express only low levels of surface MHC class II. The explosive in vivo response of the airway DC network to local challenge with inflammatory stimuli is severely attenuated during infancy and, in addition, their capacity to respond in vitro to “maturation” signals from GM-CSF is blunted, which suggests that they may be under some form of active suppression within this microenvironment during early life.

These findings, if applicable to humans, provide a plausible explanation for both the increased susceptibility of infants to respiratory viral infections and may also explain the low efficiency (relative to adults) of development of T cell memory to viral infections during this life phase. Additionally, they point to potentially important new areas for research in relation to the aetiology of atopic asthma, including expression of persistent disease in later life.

In this latter context, it is becoming clear that the development of long term immunological memory against the inhalant allergens, which are major trigger factors for atopic asthma in later life, occurs during the early postnatal period (reviewed by Holtet al 11). Furthermore, protection against allergic sensitisation in the form of development of stable Th2 polarised immunological memory requires allergen specific signalling to the T cell system in a format which selectively promotes Th1 immunity. Given, firstly, that the portal of entry of the relevant (inhalant) allergens is via the respiratory tract and, secondly, that the only APC present to acquire and transmit these allergenic signals to the T cell system are respiratory tract DCs, it is highly likely that the kinetics of postnatal maturation of this DC network is a rate limiting factor in the development of quantitative and qualitative aspects of T cell immunity to these allergens.

In the current issue of Thorax, Tschernig and colleagues12 provide the first tentative evidence that the ontogeny of respiratory tract DCs in humans may follow a similar pattern to that observed in animal models. They report that dendritiform cells expressing either HLA-DR or CD1a are rare within the airway mucosa of infants under 1 year of age who died of SIDS or acute trauma. In contrast, HLA-DR+ DC-like cells were present in airway sections from infants who died of respiratory infection and from older children who died from acute trauma.

This preliminary study requires confirmation including, in particular, more detailed characterisation of the surface phenotype of the putative DCs and further sampling during the preweaning period in order to obtain information relating to the kinetics of the developmental process. However, taken together with earlier findings indicating a general paucity of HLA-DR expression in the human airway mucosa during early infancy,13 it suggests that, analogous to experimental animals, human respiratory tract DC networks develop almost entirely postnatally.

It is also of interest to note the increased frequency of putative DCs in airway tissues in association with respiratory infection.12 This observation is consistent with the results of animal model studies which suggest that the postnatal maturation of respiratory tract DC networks may be “driven” by direct stimulation from inhaled irritant stimuli, including that derived from microbial sources.9 ,10 Such a mechanism provides one potential avenue for the “bystander” effects of respiratory infections on the postnatal development of T cell immunity to other classes of airborne antigens, including inhalant allergens.14