Apoptosis Regulators Bim and Fas Function Concurrently to Control Autoimmunity and CD8+ T Cell Contraction

• Published in: Immunity (Cambridge, Mass.) Mass.), 2008-02, Vol.28 (2), p.218-230
• Main Authors: Weant, Ashley E., Michalek, Ryan D., Khan, Islam U., Holbrook, Beth C., Willingham, Mark C., Grayson, Jason M.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - immunology; Apoptosis Regulatory Proteins - metabolism; Autoimmunity; Bcl-2-Like Protein 11; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - physiology; Cell Division; Cell Survival; fas Receptor - deficiency; fas Receptor - immunology; fas Receptor - metabolism; Immune system; Lymphatic Diseases - genetics; Lymphatic Diseases - immunology; Lymphocytes; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - virology; Lymphocytic choriomeningitis virus - immunology; Membrane Proteins - deficiency; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; MOLIMMUNO; Mutation; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - immunology; Proto-Oncogene Proteins - metabolism; Receptors, Antigen, T-Cell - immunology; Rodents; T cell receptors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.12.014

Throughout most of adult life, lymphocyte number remains constant because of a balance of proliferation and apoptosis. Mutation of Bim, a proapoptotic protein in the intrinsic death pathway, or Fas, a tumor necrosis factor receptor (TNFR) superfamily member of the extrinsic pathway, results in late-onset autoimmunity and increased antigen-specific CD8+ T cell responses during viral infection. However, virus-specific immune responses eventually return to amounts comparable to those for nonmutant mice. Here, we show that loss of both Bim and Fas function resulted in a synergistic disruption of lymphoid homeostasis, rapid-onset autoimmunity, and organ-specific blocks on contraction of antiviral immune responses. When lymphocytic choriomeningitis virus (LCMV)-specific immune responses were quantitated, double-mutant mice had 100-fold more antigen-specific memory CD8+ T cells in their lymph nodes than wild-type mice. Our results demonstrate that multiple death pathways function concurrently to prevent autoimmunity and downsize T cell responses.