Fas Receptor Expression in Germinal-Center B Cells Is Essential for T and B Lymphocyte Homeostasis

Fas is highly expressed in activated and germinal center (GC) B cells but can potentially be inactivated by misguided somatic hypermutation. We employed conditional Fas-deficient mice to investigate the physiological functions of Fas in various B cell subsets. B cell-specific Fas-deficient mice deve...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2008-10, Vol.29 (4), p.615-627
Main Authors: Hao, Zhenyue, Duncan, Gordon S., Seagal, Jane, Su, Yu-Wen, Hong, Claire, Haight, Jillian, Chen, Nien-Jung, Elia, Andrew, Wakeham, Andrew, Li, Wanda Y., Liepa, Jennifer, Wood, Geoffrey A., Casola, Stefano, Rajewsky, Klaus, Mak, Tak W.
Format: Article
Language:English
Subjects:
Animals
Antigens
Antigens, CD - immunology
Antigens, CD - metabolism
Autoimmune diseases
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
B7-1 Antigen - immunology
B7-1 Antigen - metabolism
CD28 Antigens - immunology
CD28 Antigens - metabolism
CD40 Antigens - immunology
CD40 Antigens - metabolism
Cell Communication
Cell Differentiation
Cell Proliferation
CELLIMMUNO
CTLA-4 Antigen
Cytokines - blood
fas Receptor - deficiency
fas Receptor - immunology
fas Receptor - metabolism
Germinal Center - immunology
Germinal Center - metabolism
Homeostasis
Immune system
Lymphocyte Activation
Medical research
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Rodents
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
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Summary:Fas is highly expressed in activated and germinal center (GC) B cells but can potentially be inactivated by misguided somatic hypermutation. We employed conditional Fas-deficient mice to investigate the physiological functions of Fas in various B cell subsets. B cell-specific Fas-deficient mice developed fatal lymphoproliferation due to activation of B cells and T cells. Ablation of Fas specifically in GC B cells reproduced the phenotype, indicating that the lymphoproliferation initiates in the GC environment. B cell-specific Fas-deficient mice also showed an accumulation of IgG1 + memory B cells expressing high amounts of CD80 and the expansion of CD28-expressing CD4 + Th cells. Blocking T cell-B cell interaction and GC formation completely prevented the fatal lymphoproliferation. Thus, Fas-mediated selection of GC B cells and the resulting memory B cell compartment is essential for maintaining the homeostasis of both T and B lymphocytes.
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2008.07.016