ABSTRACT
Although Foxp3(+) regulatory T cells (Tregs) are thought to express autoreactive TCRs, it is not clear how individual TCRs influence Treg development, phenotype, and function in vivo. We have generated TCR transgenic mice (termed SFZ70 mice) using Tcra and Tcrb genes cloned from an autoreactive CD4(+) T cell isolated from a Treg-deficient scurfy mouse. The SFZ70 TCR recognizes a cutaneous autoantigen and drives development of both conventional CD4(+) Foxp3(-) T cells (T(conv)) and Foxp3(+) Tregs. SFZ70 Tregs display an activated phenotype evidenced by robust proliferation and expression of skin-homing molecules such as CD103 and P-selectin ligand. Analysis of Foxp3-deficient SFZ70 mice demonstrates that Tregs inhibit T(conv) cell expression of tissue-homing receptors and their production of proinflammatory cytokines. In addition, Treg suppression of SFZ70 T(conv) cells can be overcome by nonspecific activation of APCs. These results provide new insights into the differentiation and function of tissue-specific Tregs in vivo and provide a tractable system for analyzing the molecular requirements of Treg-mediated tolerance toward a cutaneous autoantigen.
Subject(s)
Autoantigens/metabolism , Autoimmune Diseases/prevention & control , Cell Differentiation/immunology , Forkhead Transcription Factors/biosynthesis , Immune Tolerance/genetics , Receptors, Antigen, T-Cell, alpha-beta/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , Animals , Autoantigens/genetics , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , Cell Differentiation/genetics , Cells, Cultured , Coculture Techniques , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Forkhead Transcription Factors/genetics , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphopenia/genetics , Lymphopenia/immunology , Lymphopenia/prevention & control , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/physiology , Skin/immunology , Skin/metabolism , Skin/pathology , T-Lymphocytes, Regulatory/metabolism , Thymus Gland/immunology , Thymus Gland/metabolism , Thymus Gland/pathology , Transcription, Genetic/immunologyABSTRACT
The adapter proteins DAP12 and FcRgamma associate with a wide spectrum of receptors in a variety of innate immune cells to mediate intracellular signaling pathways when their cognate receptor is engaged. These adapter proteins are coupled to their receptors through charged residues within the transmembrane regions of the adapter and receptor. DAP12 and FcRgamma contain specific protein domains (referred to as immunoreceptor tyrosine-based activation motifs) that serve as the substrates and docking sites for kinases, allowing amplification of intracellular signaling reactions. Recent research has broadened the repertoire of receptors that utilize these adapters for signaling to include not only novel immunoglobulin superfamily members but also cytokine receptors, integrins, and other adhesion molecules. There is abundant evidence that these multifunctional signaling adapters also mediate inhibitory activity, downmodulating signaling from Toll-like receptors and other heterologous receptors. In this review, we discuss the newly described receptors that utilize DAP12 and/or FcRgamma adapters to modulate innate immune responses.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Membrane Proteins/metabolism , Myeloid Cells/metabolism , Receptors, IgG/metabolism , Adaptor Proteins, Signal Transducing/immunology , Animals , Humans , Immunity, Innate , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/immunology , Myeloid Cells/cytology , Myeloid Cells/immunology , Protein Interaction Domains and Motifs , Receptors, IgG/immunology , Signal Transduction/immunology , Tyrosine/metabolismABSTRACT
Several subsets of Foxp3(+) regulatory T cells (T(reg) cells) work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of T(reg) cells remain obscure. We show that in response to interferon-gamma, Foxp3(+) T(reg) cells upregulated the T helper type 1 (T(H)1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on T(reg) cells, and T-bet(+) T(reg) cells accumulated at sites of T(H)1 cell-mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of T(reg) cells during type 1 inflammation. Thus, in a subset of CD4(+) T cells, the activities of the transcription factors Foxp3 and T-bet are overlaid, which results in T(reg) cells with unique homeostatic and migratory properties optimized for the suppression of T(H)1 responses in vivo.
