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Bim and Fas Function Concurrently to Control Autoimmunity and CD8+ T Cell Contraction
Author(s) -
Weant Ashley,
Michalek Ryan D,
Khan Islam U,
Holbrook Beth C,
Willingham Mark C,
Grayson Jason M
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.663.25
Subject(s) - cd8 , immune system , autoimmunity , immunology , t cell , biology , fas receptor , spleen , apoptosis , programmed cell death , antigen , genetics
Throughout most of adult life lymphocyte number remains constant due to a balance between proliferation and death. To determine whether loss of genes in both the extrinsic and intrinsic cell death pathways would exacerbate defects in immune homeostasis we created Bim −/− Fas lpr/lpr mice. Mice were born at the expected Mendelian ratios and appeared to develop normally. However, by 14 weeks of age they developed massive lymphadenopathy compared to either single mutant or wildtype animals. Loss of both Bim and Fas also resulted in dramatic increases in autoantibodies and deposition of immunoglobulin in the kidneys. When antiviral immune responses were quantitated following acute LCMV infection, double mutants contained 100‐fold more antigen‐specific memory CD8 + T cells in their lymph nodes compared to wildtype mice. This increase in cell numbers was not the result of increased proliferation, therefore it must be due to decreased apoptosis. Although contraction was blocked in the lymph nodes of double mutants, it was similar to the Bim parental strain in the spleen and liver. Following chronic LCMV infection, the number of antigen‐specific CD8 + T cells was similar between Bim −/− Fas lpr/lpr and the Bim −/− parental genotype. Our results demonstrate that multiple death pathways function concurrently to prevent autoimmunity and downsize T cell responses. Supported by ACS‐ #RSG‐04‐066‐01‐MBC to Jason Grayson.