ABSTRACT
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 beta receptor (LTbetaR). 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-betaR 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 LTbetaR-CXCR5 signaling axis.
Subject(s)
Antigens/immunology , Lymphoid Tissue/growth & development , Lymphotoxin beta Receptor/physiology , Nasal Mucosa/growth & development , Receptors, CXCR5/physiology , Signal Transduction/immunology , Adoptive Transfer , Aging/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antigens, Surface/metabolism , B-Lymphocytes/immunology , CD40 Ligand/immunology , Cell Adhesion Molecules/metabolism , Cell Count , Cell Movement/immunology , Germ-Free Life/immunology , Lymph Nodes/cytology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocytes/cytology , Lymphoid Tissue/blood supply , Lymphoid Tissue/pathology , Lymphotoxin-alpha/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Mucoproteins , Nasal Mucosa/blood supply , Nasal Mucosa/pathology , Propionibacterium acnes/immunology , Spleen/cytology , Tumor Necrosis Factor Ligand Superfamily Member 14/antagonists & inhibitors , Venules/growth & development , Venules/metabolism , Venules/pathologyABSTRACT
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.
