Allergic airway diseases such as asthma are caused by a failure of the immune system to induce tolerance against environmental Ags. The underlying molecular and cellular mechanisms that initiate tolerance are only partly understood. In this study, we demonstrated that a CCR7-dependent migration of both CD103+ and CD103− lung dendritic cells (DC) to the bronchial lymph node (brLN) is indispensable for this process. Although inhaled Ag is amply present in the brLN of CCR7-deficient mice, T cells cannot be tolerized because of the impaired migration of Ag-carrying DC and subsequent transport of Ag from the lung to the draining lymph node. Consequently, the repeated inhalation of Ag protects wild-type but not CCR7-deficient mice from developing allergic airway diseases. Thus, the continuous DC-mediated transport of inhaled Ag to the brLN is critical for the induction of tolerance to innocuous Ags.

Nose-associated lymphoid tissue (NALT) in the rodent upper respiratory tract develops postnatally and is considered to be independent of several factors known to be involved in the organogenesis of LN and Peyer's patches (PP). In this study we demonstrate that at least two different pathways result in NALT development. Following NALT anlage formation the intrinsic pathway relies on a signaling cascade including those mediated through the chemokine receptor CXCR5 and the lymphotoxin b receptor (LTbR). This allows for the formation of high endothelial venules and thereby the recruitment of lymphocytes into NALT. Alternatively, high endothelial venule formation and lymphocyte recruitment can be induced in the NALT anlage by environmental signals, which are independent of LT-bR and chemokine receptor CXCR5 signaling but in part rely on CD40 ligand. Thus, our study identifies a novel mechanism that facilitates the rescue of NALT development at late stages in adult life independent of the canonical LTbR-CXCR5 signaling axis.Key words: Chemokines . Developmental immunology . Lymphoid organs Supporting Information available online IntroductionMucosal surfaces are equipped with dedicated mucosa-associated lymphoid tissues that facilitate the induction of mucosal immune responses. Nose-associated lymphoid tissue (NALT) in the rodent upper respiratory tract belongs to these specialized structures [1]. Due to its close proximity to entry sites of foreign and infectious agents NALT is an important inductive tissue for the generation of long lasting mucosal immunity in the upper respiratory tract and in the oral cavity [2][3][4][5][6]. NALT represents a paired lymphoid structure localized cranially to the soft palate at the bifurcated pharyngeal duct of rodents. Each part of the organ is composed of follicle-associated epithelium, high endothelial venules (HEV), T-and B-cell-enriched areas as well as DC [2].In contrast to most secondary lymphoid organs, the development of NALT initiates postnatally [7][8][9]. Furthermore, NALT undergoes substantial changes at weaning and its structural differentiation seems to be completed 6 wk after birth indicating that NALT development might be influenced by environmental stimuli [7]. The conventional model of secondary lymphoid organ development presumes the interplay between stromal organizer cells and CD45 receptors CXCR5 and CCR7. NALT development is initiated independently of the majority of factors known to be involved in the interaction of stromal organizer and LTi cells, such as LTa, LTb, LTbR, TNF, TNFRp55, IL7-R, RORg, TRANCE, CXCL13, CCL19 and CCL21 [8][9][10][11], [8,9,12,13]. The only molecule identified so far and believed to be essential for the initiation of the NALT anlage formation is the transcriptional regulator ''inhibitor of DNA binding 2'' (Id2) [10]. Although LTi cells are missing in Id2 À/À mice it seems unlikely that the lack of this cell population is responsible for the absence of NALT in Id2 À/À mice as NALT develops in RORg À/À mice, which also lack LTi cells ...