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

Abstract

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. We sought to determine whether TACI and CD40 cooperate in inducing class switch recombination and immunoglobulin production. 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(1) and IgE production was measured by means of ELISA. mRNA for Cgamma(1) and Cepsilon germ-line transcripts, activation-induced cytidine deaminase, and mature gamma(1) and epsilon transcripts were measured by means of RT-PCR. Plasmablasts were enumerated by using syndecan-1/CD138 staining. Interferon regulatory factor 4, B lymphocyte-induced maturation protein 1, and IL6 mRNA expression was measured by using quantitative PCR. TACI ligation enhanced IgG(1) 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. TACI and CD40 signaling converge to promote B-cell differentiation into plasmablasts. Our data suggest that TACI dysfunction could contribute to the impaired antibody response to T-dependent antigens in common variable immunodeficiency.