ABSTRACT
Defense against attaching-and-effacing bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. Although CD4(+) and NKp46(+) innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete mice of specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the attaching-and-effacing pathogen Citrobacter rodentium. We found that the signaling receptor Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b(+) cDCs were an obligate source of IL-23 required for survival after infection with C. rodentium, but CD103(+) cDCs dependent on the transcription factor Batf3 were not. Our results demonstrate a nonredundant function for CD11b(+) cDCs in the response to pathogens in vivo.
Subject(s)
Citrobacter rodentium/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Receptor, Notch2/metabolism , Animals , Antigens, CD/metabolism , CD11b Antigen/metabolism , Cell Differentiation/genetics , Cell Differentiation/immunology , Dendritic Cells/cytology , Enterobacteriaceae Infections/immunology , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae Infections/mortality , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Interleukin-23/metabolism , Intestinal Mucosa/microbiology , Lectins, C-Type/metabolism , Lymphotoxin beta Receptor/genetics , Lymphotoxin beta Receptor/metabolism , Mice , Mice, Transgenic , Minor Histocompatibility Antigens , Receptor, Notch2/deficiency , Receptors, Cell Surface/metabolism , Signal Transduction , Spleen/immunology , Transcription Factors/genetics , Transcription Factors/metabolism , Wound Healing/genetics , Wound Healing/immunologyABSTRACT
B cell tolerance to self-antigen is critical to preventing antibody-mediated autoimmunity. Previous work using B cell antigen receptor transgenic animals suggested that self-antigen-specific B cells are either deleted from the repertoire, enter a state of diminished function termed anergy, or are ignorant to the presence of self-antigen. These mechanisms have not been assessed in a normal polyclonal repertoire because of an inability to detect rare antigen-specific B cells. Using a novel detection and enrichment strategy to assess polyclonal self-antigen-specific B cells, we find no evidence of deletion or anergy of cells specific for antigen not bound to membrane, and tolerance to these types of antigens appears to be largely maintained by the absence of T cell help. In contrast, a combination of deleting cells expressing receptors with high affinity for antigen with anergy of the undeleted lower affinity cells maintains tolerance to ubiquitous membrane-bound self-antigens.
Subject(s)
Autoantigens/immunology , B-Lymphocytes/immunology , Clonal Anergy/immunology , Clonal Deletion/immunology , Adoptive Transfer , Animals , Arthritis/immunology , Arthritis/metabolism , Autoantigens/metabolism , B-Lymphocytes/metabolism , Cell Membrane/immunology , Cell Membrane/metabolism , Clone Cells/immunology , Clone Cells/metabolism , Female , Flow Cytometry , Glycosylphosphatidylinositols/chemistry , Glycosylphosphatidylinositols/immunology , Glycosylphosphatidylinositols/metabolism , Lymphocyte Count , Male , Mice , Mice, 129 Strain , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Ovalbumin/chemistry , Ovalbumin/immunology , Ovalbumin/metabolism , Protein Multimerization , Receptors, Antigen, B-Cell/immunology , Receptors, Antigen, B-Cell/metabolismABSTRACT
Rheumatoid arthritis develops in association with a defect in peripheral CD4(+) T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4(+) T cell clonal anergy induction. We therefore explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4(+) T cells in the setting of selective T cell lymphopenia. CD4(+) T cell recognition of self-GPI peptide/MHC class II complexes in normal murine hosts did not lead to arthritis and instead caused those T cells to develop a Folate receptor 4(hi)CD73(hi) anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3(+)CD4(+) regulatory T cells could not make GPI-specific CD4(+) T cells anergic and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3(+)CD4(+) regulatory T cells are insufficient to functionally inactivate all autoreactive CD4(+) T cells that encounter self-Ag.
