Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction.
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.
Weant
Ashley E
AE
Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Michalek
Ryan D
RD
Khan
Islam U
IU
Holbrook
Beth C
BC
Willingham
Mark C
MC
Grayson
Jason M
JM
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D002455:Cell Division; D002470:Cell Survival; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D019014:fas Receptor / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor