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*
Department of Developmental Genetics, Chiba University Graduate School of Medicine, Chiba, Japan; and
Department of Orthopedics, Chiba University School of Medicine, Chiba, Japan
We examined the role of c-Fos in the differentiation of mature B
cells into IgG-producing cells using transgenic mice carrying the
c-fos gene under the control of the
IFN-
/ß-inducible Mx promoter (Mx-c-fos) or the
constitutive H-2Kb promoter (H2-c-fos).
Splenic B cells from Mx-c-fos mice were cultured with
LPS and rIL-4, and IgG1+ B cells were developed in the
culture after day 3. When IFN-
/ß was added to the culture from day
2, development of IgG1+ B cells was perturbed, and the
number of apoptotic cells increased within 24 h, suggesting that
c-Fos induces apoptosis in Ig class-switching B cells. To confirm the
effect of c-Fos on B cell differentiation in vivo,
H2-c-fos mice were immunized with DNP-OVA. The mice
produced primary IgM, but not IgG, anti-DNP Ab in serum and failed
to generate germinal centers in spleen. The perturbation of germinal
center formation in H2-c-fos mice was rescued by mating
them with transgenic mice carrying the bcl-2 gene with
the Ig promoter. However, primary IgG1 anti-DNP Ab production was
still suppressed in doubly transgenic mice, suggesting that Bcl-2 can
delay the time of c-Fos-induced apoptosis in Ig class-switching B cells
but cannot rescue the death. Since c-Fos is induced in mature B cells
reacted with Ags, and clonal deletion of self-reactive B cells in
germinal centers is insensitive to Bcl-2, these results suggest that
c-Fos plays a causal role in clonal deletion of germinal center B
cells.
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