title: The Fas-associated death domain protein is required in apoptosis and TLR-induced proliferative responses in B cells.
abstract: The Fas-associated death domain protein (FADD)/Mort1 is a signaling adaptor protein which mediates the activation of caspase 8 during death receptor-induced apoptosis. Disruption of FADD in germ cells results in death receptor-independent embryonic lethality in mice. Previous studies indicated that in addition to its function in apoptosis, FADD is also required in peripheral T cell homeostasis and TCR-induced proliferative responses. In this report, we generated B cell-specific FADD-deficient mice and showed that deletion of FADD at the pro-B cell stage had minor effects on B cell development in the bone marrow, and resulted in increased splenic and lymph node B cell numbers and decreased peritoneal B1 cell numbers. As in T cells, a FADD deficiency inhibited Fas-induced apoptosis in B cells. However, B cell-proliferative responses induced by stimulation of the BCR and CD40 using anti-IgM or anti-CD40 Abs were unaffected by the absence of FADD. Further analyses revealed that FADD-deficient B cells were defective in proliferative responses induced by treatments with dsRNA and LPS which stimulate TLR3 and TLR4, respectively. Therefore, in addition to its apoptotic function, FADD also plays a role in TLR3- and TLR4-induced proliferative responses in B cells.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Hongxia Z
authors.initials: HZ
authors.lastname: Imtiyaz
authors.forename: Stephen
authors.initials: S
authors.lastname: Rosenberg
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ziaur S M
authors.initials: ZS
authors.lastname: Rahman
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Hou
authors.forename: Tim
authors.initials: T
authors.lastname: Manser
authors.forename: Jianke
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D053200:Fas-Associated Death Domain Protein; D007072:Immunoglobulin D / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000944:Antigens, Differentiation, B-Lymphocyte; D018985:Epitopes, B-Lymphocyte; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4