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Normal B Cell Homeostasis Requires B Cell Activation Factor Production by Radiation-resistant Cells

Leonid Gorelik, Kevin Gilbride, Max Dobles, Susan L. Kalled, Daniel Zandman and Martin L. Scott

Biogen Inc., Cambridge, MA 02142

Address correspondence to Leonid Gorelik, Biogen Inc., 14 Cambridge Center, Cambridge, MA 02142. Phone: (617) 679-3297; Fax: (617) 679-3148; email: Leonid_Gorelik{at}biogen.com

The cellular source of B cell activation factor (BAFF) required for peripheral B cell survival/maturation is unknown. To determine the nature of BAFF-producing cells we established and analyzed reciprocal bone marrow (BM) chimeras with wild-type (WT) and BAFF-deficient mice. The results revealed that BAFF production by radiation-resistant stromal cells is completely sufficient to provide a necessary signal for B cell survival/maturation, as BAFF^-/- BM cells transferred into lethally irradiated WT mice gave rise to normal numbers of follicular (FO) and marginal zone (MZ) B cell subpopulations. On the other hand, transfer of WT BM into BAFF^-/- lethally irradiated mice resulted only in minimal reconstitution of mature FO B cells and no restoration of MZ B cells. Thus, in the absence of BAFF^+/+ stromal cells, BAFF production by BM-derived cells, presumably by macrophages, dendritic cells, and/or neutrophils, was not at all sufficient to support normal B cell homeostasis. Interestingly, immunization of both types of chimeras stimulated high levels of antigen-specific antibody secretion, indicating that either stromal cell– or hematopoietic cell–derived BAFF is sufficient for B cell antibody responses.

Key Words: BAFF • B cells • homeostasis • bone marrow • stromal cells

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