ABSTRACT
In this study, we demonstrated a new airway Ag sampling site by analyzing tissue sections of the murine nasal passages. We revealed the presence of respiratory M cells, which had the ability to take up OVA and recombinant Salmonella typhimurium expressing GFP, in the turbinates covered with single-layer epithelium. These M cells were also capable of taking up respiratory pathogen group A Streptococcus after nasal challenge. Inhibitor of DNA binding/differentiation 2 (Id2)-deficient mice, which are deficient in lymphoid tissues, including nasopharynx-associated lymphoid tissue, had a similar frequency of M cell clusters in their nasal epithelia to that of their littermates, Id2(+/-) mice. The titers of Ag-specific Abs were as high in Id2(-/-) mice as in Id2(+/-) mice after nasal immunization with recombinant Salmonella-ToxC or group A Streptococcus, indicating that respiratory M cells were capable of sampling inhaled bacterial Ag to initiate an Ag-specific immune response. Taken together, these findings suggest that respiratory M cells act as a nasopharynx-associated lymphoid tissue-independent alternative gateway for Ag sampling and subsequent induction of Ag-specific immune responses in the upper respiratory tract.
Subject(s)
Antigens, Bacterial/administration & dosage , Lymphoid Tissue/immunology , Nasal Mucosa/immunology , Nasopharynx/immunology , Plant Lectins/administration & dosage , Turbinates/immunology , Administration, Inhalation , Animals , Antigens, Bacterial/immunology , Epithelial Cells/immunology , Epithelial Cells/microbiology , Epithelial Cells/ultrastructure , Lymphocyte Count , Lymphoid Tissue/microbiology , Lymphoid Tissue/ultrastructure , Mice , Mice, 129 Strain , Mice, Inbred BALB C , Mice, Knockout , Nasal Cavity/immunology , Nasal Cavity/microbiology , Nasal Cavity/ultrastructure , Nasal Mucosa/microbiology , Nasal Mucosa/ultrastructure , Nasopharynx/microbiology , Nasopharynx/ultrastructure , Plant Lectins/biosynthesis , Plant Lectins/immunology , Salmonella typhimurium/immunology , Streptococcus pyogenes/immunology , Turbinates/microbiology , Turbinates/ultrastructure , Ulex/immunology , Wheat Germ Agglutinins/immunologyABSTRACT
Microfold cells (M cells) are specialized epithelial cells situated over Peyer's patches (PP) and other organized mucosal lymphoid tissues that transport commensal bacteria and other particulate Ags into intraepithelial pockets accessed by APCs. The TNF superfamily member receptor activator of NF-kappaB ligand (RANKL) is selectively expressed by subepithelial stromal cells in PP domes. We found that RANKL null mice have <2% of wild-type levels of PP M cells and markedly diminished uptake of 200 nm diameter fluorescent beads. Ab-mediated neutralization of RANKL in adult wild-type mice also eliminated most PP M cells. The M cell deficit in RANKL null mice was corrected by systemic administration of exogenous RANKL. Treatment with RANKL also induced the differentiation of villous M cells on all small intestinal villi with the capacity for avid uptake of Salmonella and Yersinia organisms and fluorescent beads. The RANK receptor for RANKL is expressed by epithelial cells throughout the small intestine. We conclude that availability of RANKL is the critical factor controlling the differentiation of M cells from RANK-expressing intestinal epithelial precursor cells.
