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1.  Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF 
The Journal of Experimental Medicine  2013;210(10):1977-1992.
Alveolar macrophages differentiate from fetal monocytes in a GM-CSF–dependent fashion and colonize the alveolar space within a few days after birth.
Tissue-resident macrophages can develop from circulating adult monocytes or from primitive yolk sac–derived macrophages. The precise ontogeny of alveolar macrophages (AMFs) is unknown. By performing BrdU labeling and parabiosis experiments in adult mice, we found that circulating monocytes contributed minimally to the steady-state AMF pool. Mature AMFs were undetectable before birth and only fully colonized the alveolar space by 3 d after birth. Before birth, F4/80hiCD11blo primitive macrophages and Ly6ChiCD11bhi fetal monocytes sequentially colonized the developing lung around E12.5 and E16.5, respectively. The first signs of AMF differentiation appeared around the saccular stage of lung development (E18.5). Adoptive transfer identified fetal monocytes, and not primitive macrophages, as the main precursors of AMFs. Fetal monocytes transferred to the lung of neonatal mice acquired an AMF phenotype via defined developmental stages over the course of one week, and persisted for at least three months. Early AMF commitment from fetal monocytes was absent in GM-CSF–deficient mice, whereas short-term perinatal intrapulmonary GM-CSF therapy rescued AMF development for weeks, although the resulting AMFs displayed an immature phenotype. This demonstrates that tissue-resident macrophages can also develop from fetal monocytes that adopt a stable phenotype shortly after birth in response to instructive cytokines, and then self-maintain throughout life.
PMCID: PMC3782041  PMID: 24043763
2.  Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33 
The Journal of Experimental Medicine  2012;209(8):1505-1517.
IL-1α promotes a cascade of cytokine production from epithelial cells culminating in Th2 immunity to house dust mite allergens.
House dust mite (HDM) is one of the most common allergens worldwide. In this study, we have addressed the involvement of IL-1 in the interaction between HDM and the innate immune response driven by lung epithelial cells (ECs) and dendritic cells (DCs) that leads to asthma. Mice lacking IL-1R on radioresistant cells, but not hematopoietic cells, failed to mount a Th2 immune response and did not develop asthma to HDM. Experiments performed in vivo and in isolated air–liquid interface cultures of bronchial ECs showed that TLR4 signals induced the release of IL-1α, which then acted in an autocrine manner to trigger the release of DC-attracting chemokines, GM-CSF, and IL-33. Consequently, allergic sensitization to HDM was abolished in vivo when IL-1α, GM-CSF, or IL-33 was neutralized. Thymic stromal lymphopoietin (TSLP) became important only when high doses of allergen were administered. These findings put IL-1α upstream in the cytokine cascade leading to epithelial and DC activation in response to inhaled HDM allergen.
PMCID: PMC3409497  PMID: 22802353
3.  Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen 
The Journal of Experimental Medicine  2010;207(10):2097-2111.
It is unclear how Th2 immunity is induced in response to allergens like house dust mite (HDM). Here, we show that HDM inhalation leads to the TLR4/MyD88-dependent recruitment of IL-4 competent basophils and eosinophils, and of inflammatory DCs to the draining mediastinal nodes. Depletion of basophils only partially reduced Th2 immunity, and depletion of eosinophils had no effect on the Th2 response. Basophils did not take up inhaled antigen, present it to T cells, or express antigen presentation machinery, whereas a population of FceRI+ DCs readily did. Inflammatory DCs were necessary and sufficient for induction of Th2 immunity and features of asthma, whereas basophils were not required. We favor a model whereby DCs initiate and basophils amplify Th2 immunity to HDM allergen.
PMCID: PMC2947072  PMID: 20819925
4.  The lung vascular filter as a site of immune induction for T cell responses to large embolic antigen 
The Journal of Experimental Medicine  2009;206(12):2823-2835.
The bloodstream is an important route of dissemination of invading pathogens. Most of the small bloodborne pathogens, like bacteria or viruses, are filtered by the spleen or liver sinusoids and presented to the immune system by dendritic cells (DCs) that probe these filters for the presence of foreign antigen (Ag). However, larger pathogens, like helminths or infectious emboli, that exceed 20 µm are mostly trapped in the vasculature of the lung. To determine if Ag trapped here can be presented to cells of the immune system, we used a model of venous embolism of large particulate Ag (in the form of ovalbumin [OVA]-coated Sepharose beads) in the lung vascular bed. We found that large Ags were presented and cross-presented to CD4 and CD8 T cells in the mediastinal lymph nodes (LNs) but not in the spleen or liver-draining LNs. Dividing T cells returned to the lungs, and a short-lived infiltrate consisting of T cells and DCs formed around trapped Ag. This infiltrate was increased when the Toll-like receptor 4 was stimulated and full DC maturation was induced by CD40 triggering. Under these conditions, OVA-specific cytotoxic T lymphocyte responses, as well as humoral immunity, were induced. The T cell response to embolic Ag was severely reduced in mice depleted of CD11chi cells or Ly6C/G+ cells but restored upon adoptive transfer of Ly6Chi monocytes. We conclude that the lung vascular filter represents a largely unexplored site of immune induction that traps large bloodborne Ags for presentation by monocyte-derived DCs.
PMCID: PMC2806611  PMID: 19858325

Results 1-4 (4)