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

被引:71
作者
Castigli, Emanuela
Wilson, Stephen A.
Elkhal, Abdallah
Ozcan, Esra
Garibyan, Lilit
Geha, Raif S.
机构
[1] Childrens Hosp, Div Immunol, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA
关键词
CD40; transmembrane activator and calcium modulator and cyclophilin ligand interactor; common variable immunodeficiency; plasma cell; immunoglobulin; B cells;
D O I
10.1016/j.jaci.2007.06.012
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:885 / 891
页数:7
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