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c-Fos Induces Apoptosis in Germinal Center B Cells¹

Kunimasa Inada^*,, Seiji Okada^*, Janyaporn Phuchareon^2,*, Masahiko Hatano^*, Toyohiko Sugimoto^*, Hideshige Moriya and Takeshi Tokuhisa^3,*

^* 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-2K^b 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.