Transmembrane activator, calcium modulator, and cyclophilin ligand interactor drives plasma cell differentiation in LPS-activated B cells.

Abstract

Transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) expression on B cells is upregulated by Toll-like receptor (TLR) 4. We sought to examine whether TACI synergizes with TLR4 in driving immunoglobulin production by B cells and to examine the mechanism of this synergy. Purified mouse naive B cells were stimulated with the TACI ligand a proliferation-inducing ligand (APRIL) and with suboptimal concentrations of the TLR4 ligand LPS in the presence or absence of IL-4. Immunoglobulin secretion was measured by means of ELISA. Surface IgG1-positive B cells and CD138+ plasmacytoid cells were enumerated by means of FACS. Expression of gamma1 and epsilon germline transcripts, activation-induced cytidine deaminase, and gamma1 and epsilon mature transcripts was measured by means of RT-PCR. APRIL synergized with LPS in driving B-cell proliferation and IgM, IgG1, IgG3, IgE, and IgA production. This was mediated by TACI because it was preserved in B-cell maturation antigen-/-, but not TACI-/-, B cells. APRIL and LPS synergized to promote isotype switching, as evidenced by increased expression of activation-induced cytidine deaminase and gamma1 and epsilon mature transcripts and generation of surface IgG1-positive cells. More importantly, APRIL and LPS strongly synergized to drive the plasma cell differentiation program, as evidenced by an increase in CD138+ cells and expression of B lymphocyte induced maturation protein-1 (Blimp-1), interferon regulatory factor-4 (IRF-4), and the spliced form of X-box binding protein-1 (XBP-1). TACI-/- mice had impaired IgM and IgG1 antibody responses to immunization, with a suboptimal dose of the type I T cell-independent antigen 2, 4, 6- Trinitrophenol (TNP)-LPS. These observations suggest that TACI cooperates with TLR4 to drive B-cell differentiation and immunoglobulin production in vitro and in vivo.