ABSTRACT
Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αß+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.
Subject(s)
Autoantigens/metabolism , CD8 Antigens/metabolism , CD8-Positive T-Lymphocytes/metabolism , Fas Ligand Protein/metabolism , Immune Tolerance , Lymphocyte Activation , fas Receptor/metabolism , Adoptive Transfer , Animals , Autoantigens/immunology , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/transplantation , Cells, Cultured , Down-Regulation , Fas Ligand Protein/genetics , Fas Ligand Protein/immunology , Kinetics , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Signal Transduction , fas Receptor/genetics , fas Receptor/immunologyABSTRACT
The cellular origin of CD4- CD8- (double negative, DNT) TCR-α/ß+ T cells remains unknown. Available evidence indicates that they may derive from CD8+ T cells, but most published data have been obtained using cells that bear an invariant transgenic T cell receptor that recognizes an Ag that is not present in normal mice. Here, we have used complementary fate mapping and adoptive transfer experiments to identify the cellular lineage of origin of DNT cells in wild-type mice with a polyclonal T cell repertoire. We show that TCR-α/ß+ DNT cells can be traced back to CD8+ and CD4+ CD8+ double positive cells in the thymus. We also demonstrate that polyclonal DNT cells generated in secondary lymphoid organs proliferate upon adoptive transfer and can regain CD8 expression in lymphopenic environment. These results demonstrate the cellular origin of DNT cells and provide a conceptual framework to understand their presence in pathological circumstances.
Subject(s)
CD4 Antigens/analysis , CD8 Antigens/analysis , CD8-Positive T-Lymphocytes/cytology , Lymphopoiesis , Receptors, Antigen, T-Cell, alpha-beta/analysis , T-Lymphocyte Subsets/cytology , Adoptive Transfer , Animals , CD8 Antigens/biosynthesis , CD8 Antigens/genetics , CD8-Positive T-Lymphocytes/classification , Cell Lineage , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Mice , Specific Pathogen-Free Organisms , Up-RegulationABSTRACT
Disease heterogeneity remains a major challenge for the understanding of systemic lupus erythematosus (SLE). Recent work has revealed the important role of nonimmune factors in the development of end-organ damage involvement, shifting the current paradigm that views SLE as a disease inflicted by a disturbed immune system on passive target organs. Here, we discuss the pathogenesis of lupus nephritis in a comprehensive manner, by incorporating the role that target organs play by withstanding and modulating the local inflammatory response. Moreover, we consider the effects that genetic variants exert on immune and nonimmune cells in order to shape the phenotype of the disease in each affected individual.
