Immune surveillance of barrier surfaces is essential for the maintenance of tissue homeostasis and defense against pathogens. Within the lung, the conducting bronchial airways represent one of the first sites of exposure to inhaled substances and infectious agents. In allergic asthma, the inhalation of harmless environmental allergens leads to peribronchial inflammation, in which the local activation of type 2 helper T cells (Th2 cells) results in effector cytokine production that promotes pathogenesis (Holgate, 2012; Lambrecht et al., 2019). The Th2 cells are activated by antigen presenting cells (APCs) that survey the epithelial barrier and capture and present antigen. However, the types of APCs contributing to surveillance of the conducting airways are not fully characterized, and the anatomical organization that couples antigen capture to Th2 cell activation remains unclear.

The lung tissue regions around the conducting airways may be ideal sites for antigen surveillance and the initiation of immune responses. Unlike alveolar spaces, the conducting airways do not participate in gaseous exchange but serve to conduct and filter air. As inspired air passes through airway branchpoints, changes in the direction of airflow promote the deposition of particulates and the dissolution of soluble substances in the overlying mucus layer (Carvalho et al., 2011; Clarke and Yeates, 1994). In allergic asthma, eosinophils and lymphocytes are recruited to regions around the conducting airways, resulting in peribronchial inflammation (Jeffery, 1992). In several mouse models of airway infections, T and B cells accumulate in organized foci near the airways, forming induced Bronchus-Associated Lymphoid Tissue (BALT) structures (Fleige and Förster, 2017; Randall, 2010). The accumulation of immune cells in tissue regions near the conducting airways may allow streamlined access to inhaled antigens that have become deposited.

The mechanism by which antigen capture and immune activation occurs at the airways is unclear. Most studies have focused on the potential contributions of dendritic cells (DCs) to allergic inflammation in the lung (Wikstrom and Stumbles, 2007), based initially on observations that MHC-II⁺ cells with dendritic morphology were abundant along both human and rodent airways at baseline (Demedts et al., 2005; Huh et al., 2003; Lambrecht et al., 1998; von Garnier et al., 2007). Flow cytometric analysis of lung-draining lymph nodes, dissociated lung tissue enriched for the conducting airways, and the trachea also showed that DCs, gated as CD11c⁺ MHC-II⁺ cells, were able to capture, process, and present fluorescent ovalbumin (OVA) administered via the airways (del Rio et al., 2007; Fear et al., 2011; Hammad et al., 2010; Huh et al., 2003; von Garnier et al., 2007). The uptake of OVA by CD11c⁺ MHC-II⁺ cells throughout the lung has also been observed by confocal microscopy (Hoffmann et al., 2018) however, two-photon microscopy studies of CD11c-YFP reporter mice found that DCs near the conducting airways did not detectably capture soluble antigens (OVA or dextran), or particulate antigens in the form of beads (Thornton et al., 2012; Veres et al., 2011). CD11c-YFP⁺ DCs were reported to capture beads at the alveoli in a mouse model of asthma, and then were proposed to migrate to tissue regions proximal to the bronchial airways, where T cells are activated (Thornton et al., 2012). This mechanism might be relevant for the uptake and presentation of particulate antigens that reach the alveoli, but whether soluble antigen can be directly captured and presented by APCs at the conducting airways remains unclear. The presentation of soluble antigens is pertinent because it was reported that individuals allergic to aeroallergens had an increased frequency of Th2 cells that preferentially recognized soluble antigen components of aeroallergens, whereas regulatory T cells preferentially recognized particulate antigen components (Bacher et al., 2016). Developing a better understanding of the uptake and presentation of soluble antigens may therefore be of significant relevance to Th2 cell responses in asthma.

In the intestine, soluble antigen in the lumen is efficiently captured by CX3CR1⁺ macrophages in the lamina propria (Farache et al., 2013a; Farache et al., 2013b; Mazzini et al., 2014; Schulz et al., 2009). These intestinal macrophages were found to be distinct from conventional DCs (cDCs) based on functional and behavioral differences and were reported to contribute to local intestinal immunity (Hadis et al., 2011; Mazzini et al., 2014; Schreiber et al., 2013; Schulz et al., 2009). Recent gene expression and microscopy studies of the lung have identified CX3CR1⁺ interstitial macrophages (IMs) that are distinct from alveolar macrophages (AMs). Notably, subpopulation(s) of these IMs express many of the surface markers previously thought to be exclusive to DCs, such as MHC-II and CD11c (Chakarov et al., 2019; Gautier et al., 2012; Gibbings et al., 2017; Sabatel et al., 2017; Schlitzer et al., 2013; Schyns et al., 2019; Ural et al., 2020). While most studies on resident tissue macrophages have focused on comparing various macrophage populations to each other, how lung DCs and IMs compare in their behaviors and functions is yet unclear.

Here, we show that in the steady state in naïve mice, lung myeloid APCs are primarily positioned underneath the bronchial airway epithelium and are strategically enriched near some airway branchpoints where inhaled allergens are likely to deposit. We found that at these regions, the majority of inhaled soluble antigens were captured by CX3CR1⁺ CD11c⁺ MHC-II⁺ IMs rather than DCs. We observed frequent contacts between CX3CR1⁺ CD11c⁺ MHC-II⁺ IMs and DCs, suggesting the possibility of antigen transfer to DCs. Yet CX3CR1⁺ CD11c⁺ MHC-II⁺ IMs themselves were capable of antigen processing and presentation, activated T cells in vitro, and interacted with T cells recruited to the airways in an asthma model. Unlike DCs, CX3CR1⁺ CD11c⁺ MHC-II⁺ IMs did not migrate to the draining lymph node and remained lung resident. We therefore propose that CX3CR1⁺ CD11c⁺ MHC-II⁺ IMs located near the bronchial airways are tissue-resident sentinel APCs that are able to drive local allergic inflammation, whereas DCs may be more critical for priming T cell responses in lymph nodes.

This work focused on the cell types involved in antigen surveillance at the airways in the steady state to understand the early events that initiate allergic airway inflammation. Our analysis of APCs at the airways revealed an abundant population of MHC-II^hi IMs positioned under the bronchial airway epithelium that sampled soluble luminal antigen, which we term BAMs. We found that BAMs were particularly enriched in collagen-rich regions near some airway branchpoints and engaged in extensive interactions with DCs. In addition, we demonstrated that BAMs were capable of antigen presentation to T cells and interacted with recruited T cells near the airways in an allergic airway disease model. While DCs migrated to the draining lymph node, BAMs remained resident in the lung after antigen capture, even in the presence of inflammatory stimuli. These findings support a model in which BAMs may locally activate effector/memory T cells recruited to the lung, whereas migratory DCs are likely critical for T cell priming in lymph nodes.

In characterizing the localization of lung cDCs and BAMs, we found that in naïve mice, both cell types were positioned around the conducting airways, and were especially enriched at some airway branchpoints in collagen-rich regions. This positioning likely facilitates the uptake of antigens that have deposited at airway branchpoints, where airflow changes directions, leading to the activation of adaptive immune responses at these locations. We found that these sites corresponded to the regions where inflammatory clusters form in allergic airway disease models. BALT has also been observed near airway bifurcations (Bienenstock and McDermott, 2005; Randall, 2010). Our observation that BAMs and DCs were enriched near airway branchpoints in the steady state, prior to immunization, suggests that airway branchpoints are ideal sites for continuous immunosurveillance of the bronchial airway lumen, enabling the rapid local activation of antigen-specific T cells and the generation of an inflammatory response. While most of the lung is filled with alveolar space to support gaseous exchange, these collagen-rich adventitial regions of connective tissue and interstitial space in the bronchovascular bundles represent a site where immune cells may be recruited. Recent work indicates that similar interstitial spaces may be found in other organs and that the adventitial ‘cuff’ regions may generally be important sites for tissue immunity (Benias et al., 2018; Dahlgren and Molofsky, 2019).

While both BAMs and DCs are strategically positioned in the lung for immunosurveillance, they differ substantially in the efficiency of antigen uptake in the steady state. Consistent with previous imaging studies of CD11c-YFP mice (Thornton et al., 2012; Veres et al., 2011), we observed minimal fluorescent antigen uptake by CD11c-YFP⁺ DCs near the airways by microscopy. Our quantitative analysis of microscope images and flow cytometry revealed that CD11c-YFP⁺ DCs were nevertheless taking up low amounts of soluble antigen. In contrast, BAMs took up higher amounts of antigen that were readily visible by imaging. In a similar manner, IMs are superior at capturing soluble antigen from the intestinal lumen compared to DCs (Mazzini et al., 2014; Schulz et al., 2009). Although one group reported equivalent uptake of antigen by DCs and IMs in the lung (Hoffmann et al., 2018), this was likely due to contamination of their DC population, which was defined as CD11c⁺ MHC-II⁺ cells, by BAMs. We have shown here that BAMs express surface CD11c and MHC-II, yet BAMs exhibit distinct antigen uptake, morphology, and motility characteristics compared with cDCs. Considering that BAMs look more dendritic than lung cDCs and are MHC-II^hi, it is likely that the MHC-II⁺ dendritiform cells identified in rodent airways in earlier studies (Fear et al., 2011; Huh et al., 2003; von Garnier et al., 2007) were actually BAMs rather than DCs. The stellate shape of BAMs is reminiscent of recent imaging studies of IMs in other tissues, such as in the kidney (Stamatiades et al., 2016), and may facilitate antigen sampling.

We observed that BAMs engaged in frequent, extensive interactions with DCs. The punctate localization of CD169 at the interacting surface between BAMs and DCs suggests this cell contact has biological significance, given precedent for a role for CD169 in antigen transfer from macrophages to DCs in the spleen and lymph nodes that contributed to cross-presentation (van Dinther et al., 2018). Phagocytosed antigen could potentially be passed from BAMs to DCs, similar to intestinal macrophages which have been shown to pass antigen to DCs through gap junctions (Mazzini et al., 2014). Peptide-MHC complexes could also potentially exchange from BAMs to DCs through trogocytosis. BAMs could thus play an important role in immunosurveillance, both directly and through antigen transfer to DCs.

During inflammatory exposures, BAMs stay resident near the bronchial airways, whereas some DCs migrate to the draining lymph node. Consequently, BAMs may play an important role in the local activation of effector/memory T cells recruited to the lung. After initial sensitization, effector T cells were recruited to the airway interstitium where BAMs were abundant as early as 4–6 hr after allergen challenge and formed long interactions with BAMs, reminiscent of activating interactions previously observed between T cells and DCs in the lymph node (Mempel et al., 2004). These interactions may lead to the production of chemotactic factors that recruit additional cells to these sites forming inflammatory foci. Thus, the recruitment and activation of T cells at the bronchial airway interstitium, where BAMs display captured antigen, would provide a basis for the initiation of allergic inflammation during allergen re-exposure in sensitized individuals. In the intestine and adipose tissue, resident macrophages were also reported to activate effector T cells and shape local immunity (Cho et al., 2014; Kamada et al., 2009; Schreiber et al., 2013); BAMs may be the functional equivalent of these macrophages at the airways.

Here we reported the rapid and efficient uptake of soluble antigen across a range of sizes by BAMs, with the magnitude of antigen uptake inversely proportional to antigen size. We did not readily observe dendrite extension through the epithelial barrier by live microscopy, making this unlikely to account for the widespread antigen uptake by BAMs, and therefore suggesting that BAMs capture soluble antigens by alternative mechanism(s). Soluble antigens may instead be captured after diffusing across the airway epithelial barrier. This model may account for the reduced uptake of larger molecular weight antigens, which would be less effective at diffusing across the epithelium. In the intestine, it was reported that low molecular weight soluble antigens passed through goblet cells (McDole et al., 2012). Although few goblet cells are present in the murine lung in the steady state, whether soluble antigens could also pass through the more abundant club cells remains to be determined. The increase in goblet cells that occurs in allergic airway disease might also facilitate the passage of soluble antigens and thus further promote the inflammatory response. At sites of BALT formation, the follicle-associated epithelium containing microfold (M) cells has also been reported to facilitate the uptake of soluble antigens (Bienenstock and Befus, 1984). Alternatively, soluble antigen may pass through gaps in the airway epithelium, such as tri-junctional complexes located where three epithelial cells meet (Patton, 1992). The 200 nm bead particles that we tested would be too large to pass through the gaps in tri-junctional complexes that average 27 nm, consistent with our observation of minimal bead uptake around the airways by either BAMs or DCs. Interestingly, one study reported that very small 20 nm beads were captured by some MHC-II⁺ cells underneath the tracheal epithelium, although the majority of beads of a range of sizes were captured by AMs in the lung parenchyma (Blank et al., 2013). Indeed, we also observed that 200 nm beads were primarily captured within the alveolar spaces by AMs. Another study observed the uptake of 1000 nm beads by DCs located at the alveoli, but not by DCs located near the conducting airways (Thornton et al., 2012). In that study, previously sensitized mice were rechallenged with antigen while beads were administered, creating an inflammatory state in which monocyte-derived cells and DCs (Jenkins and Hume, 2014; Rodero et al., 2015) likely were recruited to the alveolar regions and captured beads. In the steady state, DCs are largely restricted to the regions near bronchial airways, yet monocytes have also been reported to patrol the alveoli and capture beads (Rodero et al., 2015). Overall, our work reveals that at the bronchial interstitium, small soluble antigens are preferentially captured by BAMs.

The form and size of an antigen was recently reported to affect the type of T cell responses induced, as type 2 allergic responses were primarily directed to small soluble antigens whereas regulatory T cell responses were primarily directed to particulate antigens (Bacher et al., 2016), though the mechanism was not explored. Our finding that soluble and particulate antigens are preferentially captured in different regions of the lung leads us to propose that the anatomic location of antigen uptake ultimately influences the final T cell response. The tissue signals inherent in different anatomic environments may prime divergent immune responses. In the alveoli, the abundant AMs have been proposed in several studies to dampen allergic responses (Bang et al., 2011; Mathias et al., 2013; Tang et al., 2001; Zasłona et al., 2014). Macrophages that were earlier found in the alveolar interstitium were also reported to produce IL-10 and reduce inflammation in allergic airway disease models (Bedoret et al., 2009; Kawano et al., 2016). The tissue environment at the alveoli thus appears to favor reduced inflammation in the delicate alveolar tissue, in the absence of overt infection in this region. Instead, the airways may be more permissive to the induction of inflammation as indicated by the concentration of immune responses at airway adjacent regions. Future work on the functional capacities and/or cytokine profiles of BAMs would further inform our understanding of the inflammatory milieu at the airway microenvironment.

We propose that BAMs represent a subset of IMs specialized for sampling the bronchial airway lumen. This work extends the findings of Gibbings et al., 2017 and Rodero et al., 2015 who first observed CX3CR1-GFP⁺ IMs localized near the bronchial airways. IM populations near the alveoli have also been reported in microscopy studies (Bedoret et al., 2009; Schyns et al., 2019; Tan and Krasnow, 2016). Multiple subsets of IMs have also been described based on different combinations of surface markers by flow cytometric analysis, as well as distinct transcriptional profiles (Chakarov et al., 2019; Gibbings et al., 2017; Sabatel et al., 2017; Schyns et al., 2019). There is a lack of consensus on the identification and localization of the IM subsets, and it seems likely that diverse pathogen exposures in different mouse facilities may affect baseline inflammation and the relative abundance of different subsets. This may explain, for example, why we observed few CD169^bright macrophages near the airways and nerves, whereas another group found these were abundant (Ural et al., 2020). Of note, most of our mice for this study were bred in a ‘super-barrier’ mouse facility that excludes additional pathogens compared to standard SPF facilities. Here we have focused specifically on the subpopulation of IMs localized near the bronchial airway epithelium that we found readily captures soluble inhaled antigens in naïve mice. We propose that the field consider referring to these macrophages as BAMs based on their anatomic localization near the bronchial airways, much as it has been useful to classify AMs based on their anatomic location. We found that BAMs expressed high amounts of MHC-II; were efficient at antigen capture, processing and presentation; and interacted with effector T cells in vivo; suggesting that BAMs serve as APCs near the bronchial airways. Our finding that BAMs expressed high amounts of surface MHC-II differs from a recent study by Schyns et al., 2019, which reported MHC-II⁺ CX3CR1-GFP⁺ IMs were primarily localized near the alveoli. This difference is likely due to technical differences in our imaging approaches. We imaged native GFP fluorescence in unfixed tissue allowing us to preferentially visualize CX3CR1-GFP^bright BAMs, whereas Schyns et al. used anti-GFP antibody amplification of CX3CR1-GFP signal in fixed tissue, which would have likely resulted in the visualization of a much larger population of cells with varying expression of CX3CR1-GFP, including monocytes and DCs. We also imaged thick tissue vibratome sections by two-photon microscopy whereas Schyns et al. imaged thin cryosections by confocal microscopy. We found the analysis of thick sections to be particularly useful to try to discern the cellular distribution of BAMs in unimmunized mice, whereas in thin sections the cells were too sparse.

Emerging data from microarray and RNAseq analyses have highlighted the distinct gene expression patterns of IMs, AMs and DCs in the lung (Chakarov et al., 2019; Gautier et al., 2012; Gibbings et al., 2017; Schlitzer et al., 2013; Schyns et al., 2019), which we have further elaborated here by our scRNAseq analysis of CD11c⁺ cells. Functional studies in other tissues such as the intestine have revealed distinct contributions of macrophages and DCs to immunity (Chang et al., 2013; Kamada et al., 2009; Mazzini et al., 2014; Schreiber et al., 2013; Schulz et al., 2009; Shaw et al., 2012). Here, we have shown that BAMs, as a subset of IMs, are distinct from lung cDCs in morphology, antigen uptake capacity and the ability to migrate to the draining lymph node. It is important to note that under inflammatory conditions, including in mouse models of allergic airway disease, monocytes rapidly enter lung tissue and differentiate into monocyte-derived cells that express surface markers that bear some resemblance to resident DCs and macrophages (Guilliams et al., 2013; Jakubzick et al., 2008; Plantinga et al., 2013). Although the MAR-1 antibody to FcεRI was thought to be a marker of these monocyte-derived cells, we recently established that this antibody also binds to CD64 and FcγRIV (Tang et al., 2019), and thus would also detect resident CD64⁺ macrophages. Recent studies of respiratory viral infection have also revealed the recruitment of a subpopulation of cDCs to the lung that stain with MAR-1 and express CD64 (Bosteels et al., 2020), further confounding the use of these markers to distinguish macrophages and cDCs in the context of inflammation. One microscopy study of the lungs of mice administered HDM reported an increase in the abundance of CD64⁺ “DCs” identified by CD11c and MHC-II expression (Hoffmann et al., 2018), which likely consisted of a heterogeneous mixture of cDCs, resident BAMs and monocyte-derived cells. Another study used an extensive analysis of the ratio of expression of CX3CR1-GFP and CD11c-mCherry reporters to determine the relative differentiation state of infiltrating monocytes (Sen et al., 2016). This paper showed an increase in the abundance of cells with high expression of both CX3CR1-GFP and CD11c-mCherry reporters in allergic airway inflammation models. These cells were proposed to represent differentiated monocyte-derived cells, and we speculate that the rare cells we observed that were bright for CX3CR1-GFP and CD11c-YFP reporters in naïve mice may also represent cells that had recently differentiated from monocytes. One challenge, however, in relating this study to our findings presented here is that the high expression of CX3CR1-GFP in resident BAMs versus the lower expression in monocytes was not considered in the analysis of the ratio of CX3CR1-GFP to CD11c-mCherry expression, which formed the basis of the monocyte differentiation model (Sen et al., 2016). Similar to BAMs and DCs, monocyte-derived cells have been reported to activate T cells and drive allergic inflammation (Plantinga et al., 2013). Conversely, monocyte-derived cells and IMs have also been reported to promote tolerance and dampen inflammation in the lung (Bedoret et al., 2009; Kawano et al., 2016; Sabatel et al., 2017). Although all these APCs may exhibit some overlap in their ability to activate T cells, it seems likely that these different cell types may skew T cell responses at the airways in distinct ways. Further studies with selective tools for manipulation will be needed to elucidate the specific contributions of BAMs, DCs, and monocyte-derived cells to lung immunity. While we have focused on the potential role of BAMs as APCs in immune surveillance of the bronchial airways, our findings do not exclude other potential functions of these cells. The association of some BAMs with nerves at bronchovascular bundles is likely of significance to tissue function and/or immunity. BAMs might also be involved in the clearance of epithelial cells or in the production of molecules involved in tissue homeostasis. It will be interesting for future studies to resolve the potential distinctions and functions of the various subsets of IMs recently defined in the lung.

In summary, our study demonstrates that the bronchial airways are a major site of soluble antigen capture where BAMs serve as resident sentinel immune cells. Compared to DCs, BAMs exhibited distinct morphology and enhanced soluble antigen uptake from the airways. BAMs also closely interacted with cDCs, suggesting the potential for antigen transfer between these cell types. In addition, DCs migrated to the draining lymph nodes whereas BAMs remained resident near the airways. This disparity in migratory behavior suggests a division of labor where migratory cDCs may prime naïve T cells in the lymph nodes while BAMs mediate local airway immunity. Our data demonstrate that BAMs are able to activate effector Th2 cells and interact with CD4 T cells recruited to the airways in mouse models of allergic airway disease. We propose that BAMs may play a similar role in the local activation of T cells in context of infection. Overall, BAMs are strategically positioned as sentinel APCs underlying the bronchial airway epithelium. BAMs were enriched at collagen-rich regions near some airway branchpoints, which may ultimately develop inflammatory foci when an adaptive immune response is initiated.

Relevant data are included in the manuscript figures and examples of 3D visualizations and time-lapse imaging are provided as videos. The RNAseq data have been deposited at the NCBI Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE214177 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE214177).

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Author details

1. Xin-Zi Tang

   1. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
   2. Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, United States
   3. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, United States

   Present address

   Molecular Engineering Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Biopolis, Singapore

   Contribution

   Conceptualization, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6064-8624

2. Lieselotte S M Kreuk

   1. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
   2. Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, United States

   Present address

   Department of Microbiology, University of Washington School of Medicine, Seattle, United States

   Contribution

   Validation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4906-039X

3. Cynthia Cho

   1. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
   2. Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, United States

   Present address

   Nkarta Therapeutics, South San Francisco, San Francisco, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

4. Ross J Metzger

   Department of Anatomy, University of California, San Francisco, San Francisco, United States

   Present address

   Department of Pediatrics (Cardiology), Stanford University School of Medicine, Stanford, United States

   Contribution

   Investigation, Methodology, Writing – review and editing, provided critical insights into lung anatomy and methodology; assisted with imaging of airway bifurcations

   Competing interests

   No competing interests declared

5. Christopher D C Allen

   1. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
   2. Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, United States
   3. Department of Anatomy, University of California, San Francisco, San Francisco, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   Chris.Allen@ucsf.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1879-9047

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