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Department of Microbiology and Immunology and The Kimmel Cancer Institute, Thomas Jefferson Medical College, Philadelphia, PA 19017
The TNF family cytokine B cell-activating factor belonging to the TNF family (BAFF) (BLyS) plays a fundamental role in regulating peripheral B cell survival and homeostasis. A BAFF-specific receptor (BAFF-R; BR3) appears to mediate these functions via activation of the NF-
B2 pathway. Signaling by the BAFF-R is also required to sustain the germinal center (GC) reaction. Engagement of this receptor results in the induction of Bcl-2, suggesting that this antiapoptotic factor acts downstream of the BAFF-R and NF-B2 pathway to promote peripheral B cell survival during primary and Ag-driven development. To test this idea, we created lines of mice coexpressing a Bcl-2 transgene and a signaling-deficient form of the BAFF-R derived from the B lymphopenic A/WySnJ strain. Surprisingly, although dramatically elevated numbers of B cells accumulate in the periphery of these mice, these B cells exhibit extremely perturbed primary development, formation of lymphoid microenvironments, and GC and IgG responses. Moreover, mice expressing the bcl-2 transgene alone display a loss of marginal zone B cells, an expansion of follicular B cells that appear immature, and alterations of the GC reaction. These results suggest that the BAFF-R and Bcl-2 regulate key and nonoverlapping aspects of peripheral B cell survival and development.
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