Class switch recombination (CSR) in B cells requires two signals (1
). The first is normally delivered by cytokines, which target specific CH
genes for transcription; the second is delivered in the case of T-dependent (TD) antigens by interaction of CD40 on B cells with its ligand CD40L on activated T cells. CSR is severely impaired in patients and mice deficient in CD40L or CD40 (2
), although low levels of IgG and variable levels of IgA are still detected in serum. Exposure to LPS derived from Gram-negative bacteria may account for some of this residual CSR in mice, but not in humans since LPS does not activate CSR in human B cells. EBV infection triggers CSR in human B cells independently of CD40L and CD40 (4
) and may contribute to residual CSR in humans with CD40L and CD40 deficiency.
B cell–activating factor of the TNF family (BAFF) and A proliferation–inducing ligand (APRIL) are two TNF family members that have been shown to activate CSR in human B cells (5
) and hence may contribute to residual CSR in CD40L and CD40 deficiency. BAFF is expressed mainly by monocytes and dendritic cells. APRIL is expressed in a large variety of tissues that include monocytes/macrophages, dendritic cells, and activated T cells. APRIL and BAFF both bind to two receptors, B cell maturation antigen (BCMA) and transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI), which are members of the TNF receptor family. BCMA is exclusively expressed on B cells, whereas TACI is expressed on B cells and activated T cells. A third receptor, BAFF receptor (BAFF-R), that is unique for BAFF is expressed mainly on B cells but also on T cells (6
). To identify the receptors that are involved in the induction of Ig class switching by BAFF and APRIL, we ascertained that these ligands activate CSR in mouse B cells and then examined their activity on B cells from TACI-, BCMA-, and BAFF-R–deficient mice.