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Original Article

^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
INSERM U404, Avenue Tony Garnier, 69365, Lyon, Cedex 07, France.33-4-37-28-23-9133-4-37-28-23-95

defrance{at}cervi-lyon.inserm.fr

Affinity maturation of the B cell response to antigen (Ag) takes place in the germinal centers (GCs) of secondary follicles. Two sequential molecular mechanisms underpin this process. First, the B cell repertoire is diversified through hypermutation of the immunoglobulin (Ig) variable region genes. Second, mutant B cell clones with improved affinity for Ag are positively selected by Ag and CD40 ligand (L). This selection step is contingent upon "priming" of GC B cells for apoptosis. The molecular means by which B cell apoptosis is initiated and controled in the GC remains unclear. Here, we show that GC B cell apoptosis is preceded by the rapid activation of caspase-8 at the level of CD95 death-inducing signaling complex (DISC). We found that GC B cells ex vivo display a preformed inactive DISC containing Fas-associated death domain–containing protein (FADD), procaspase-8, and the long isoform of cellular FADD-like IL-1β–converting enzyme-inhibitory protein (c-FLIP_L) but not the CD95L. In culture, c-FLIP_L is rapidly lost from the CD95 DISC unless GC B cells are exposed to the survival signal provided by CD40L. Our results suggest that (a) the death receptor signaling pathway is involved in the affinity maturation of antibodies, and (b) c-FLIP_L plays an active role in positive selection of B cells in the GC.

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

Abbreviations used in this paper: BCR, B cell receptor; c-FLIP, cellular FLICE-inhibitory protein; c-FLIP_L, long isoform of c-FLIP; c-FLIP_S, short isoform of c-FLIP; m, mitochondrial transmembrane potential; DD, death domain; DISC, death-inducing signaling complex; FADD, Fas-associated death domain–containing protein; fmk, fluoromethylketone; FLICE, FADD-like IL-1β–converting enzyme; FDC, follicular dendritic cell; GC, germinal center; HRP, horseradish peroxidase; L, ligand; PS, phosphatidylserine; RT, reverse transcription.

© 2001 The Rockefeller University Press

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