FLICE-inhibitory Protein Is a Key Regulator of Germinal Center B Cell Apoptosis

doi:10.1084/jem.193.4.447

Published online 12 February 2001.

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© The Rockefeller University Press, 0022-1007/2001/2/447/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 447-458

Original Article

FLICE-inhibitory Protein Is a Key Regulator of Germinal Center B Cell Apoptosis

Ana Hennino^a, Marion Bérard^a, Peter H. Krammer^b, and Thierry Defrance^a
^a Institut National de la Santé et de la Recherche Médicale (INSERM), U404 Immunité et Vaccination, Lyon, Cedex 07, France
^b Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany

Correspondence to: Thierry Defrance, INSERM U404, Avenue Tony Garnier, 69365, Lyon, Cedex 07, France. Tel:33-4-37-28-23-95 Fax:33-4-37-28-23-91 E-mail:defrance{at}cervi-lyon.inserm.fr.

Affinity maturation of the B cell response to antigen (Ag) takesplace in the germinal centers (GCs) of secondary follicles.Two sequential molecular mechanisms underpin this process. First,the B cell repertoire is diversified through hypermutation ofthe immunoglobulin (Ig) variable region genes. Second, mutantB cell clones with improved affinity for Ag are positively selectedby Ag and CD40 ligand (L). This selection step is contingentupon "priming" of GC B cells for apoptosis. The molecular meansby which B cell apoptosis is initiated and controled in theGC remains unclear. Here, we show that GC B cell apoptosis ispreceded by the rapid activation of caspase-8 at the level ofCD95 death-inducing signaling complex (DISC). We found thatGC B cells ex vivo display a preformed inactive DISC containingFas-associated death domain–containing protein (FADD),procaspase-8, and the long isoform of cellular FADD-like IL-1ß–convertingenzyme-inhibitory protein (c-FLIP_L) but not the CD95L. In culture,c-FLIP_L is rapidly lost from the CD95 DISC unless GC B cellsare exposed to the survival signal provided by CD40L. Our resultssuggest that (a) the death receptor signaling pathway is involvedin the affinity maturation of antibodies, and (b) c-FLIP_L playsan active role in positive selection of B cells in the GC.

Key Words: human, signal transduction, cell death, affinity maturation,B lymphocytes

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