Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation

Background: Transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is a receptor used by B cell-activating factor of the TNF family and a proliferation-inducing ligand (APRIL) to induce isotype switching independently of CD40 and is mutated in patients with common variable immunodeficiency. Objective: We sought to determine whether TACI and CD40 cooperate in inducing class switch recombination and immunoglobulin production. Methods: Naive mouse B cells were stimulated with suboptimal concentrations of anti-CD40 plus IL-4 in the presence or absence of APRIL or anti-TACI IgG, and IgE production was measured by means of ELISA. mRNA for Cy-l and C epsilon germ-line transcripts, activation-induced cytidine deaminase, and mature gamma(1) and F transcripts were measured by means of RT-PCR. Plasmablasts were enumerated by using syndecan-l/ CD138 staining. Interferon regulatory factor 4, B lymphocyte-induced maturation protein 1, and IL6 mRNA expression was measured by using quantitative PCR. Results: TACI ligation enhanced IgG, and IgE secretion by naive murine B cells stimulated by anti-CD40 plus IL-4, with little effect on B-cell proliferation or class switch recombination. In contrast, TACI ligation of anti-CD40 plus IL-4-stimulated B cells induced a significant increase in syndecans-1/CD138-positive cells. TACI ligation caused a modest but significant increase in the expression of interferon regulatory factor 4, with no detectable change in B lymphocyte-induced maturation protein 1 expression. Conclusion: TACI and CD40 signaling converge to promote B-cell differentiation into plasmablasts. Clinical implications: Our data suggest that TACI dysfunction could contribute to the impaired antibody response to T-dependent antigens in common variable immunodeficiency.