Elimination of Antigen-Presenting Cells and Autoreactive T Cells by Fas Contributes to Prevention of Autoimmunity

• Published in: Immunity (Cambridge, Mass.) Mass.), 2007-05, Vol.26 (5), p.629-641
• Main Authors: Stranges, Peter B., Watson, Jessica, Cooper, Cristie J., Choisy-Rossi, Caroline-Morgane, Stonebraker, Austin C., Beighton, Ryan A., Hartig, Heather, Sundberg, John P., Servick, Stein, Kaufmann, Gunnar, Fink, Pamela J., Chervonsky, Alexander V.
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens - immunology; Autoimmunity - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; CD11c Antigen - genetics; CD11c Antigen - metabolism; CELLCYCLE; CELLIMMUNO; Cells, Cultured; Cytotoxicity; Dendritic Cells - immunology; Dendritic Cells - metabolism; fas Receptor - genetics; fas Receptor - immunology; Gene Deletion; Gene Expression Regulation; Immunoglobulin Heavy Chains - immunology; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Mice; Mice, Transgenic; MOLIMMUNO; Peptides; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.03.016

Fas (also known as Apo-1 and CD95) receptor has been suggested to control T cell expansion by triggering T cell-autonomous apoptosis. This paradigm is based on the extensive lymphoproliferation and systemic autoimmunity in mice and humans lacking Fas or its ligand. However, with systemic loss of Fas, it is unclear whether T cell-extrinsic mechanisms contribute to autoimmunity. We found that tissue-specific deletion of Fas in mouse antigen-presenting cells (APCs) was sufficient to cause systemic autoimmunity, implying that normally APCs are destroyed during immune responses via a Fas-mediated mechanism. Fas expression by APCs was increased by exposure to microbial stimuli. Analysis of mice with Fas loss restricted to T cells revealed that Fas indeed controls autoimmune T cells, but not T cells responding to strong antigenic stimulation. Thus, Fas-dependent elimination of APCs is a major regulatory mechanism curbing autoimmune responses and acts in concert with Fas-mediated regulation of chronically activated autoimmune T cells.