Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival.

Xijun Ou, Shengli Xu, Kong-Peng Lam

Proceedings of the National Academy of Sciences of the United States of America 2012 Sep 18

filter terms:

Mutations in TNFRSF13B, better known as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), contribute to common variable immunodeficiency and autoimmunity in humans. How TACI regulates these two opposing conditions is unclear, however. TACI binds the cytokines BAFF and APRIL, and previous studies using gene KO mice indicated that loss of TACI affected only T-cell-independent antibody responses. Here we demonstrate that Taci(-/-) mice have expanded populations of T follicular helper (T(fh)) and germinal center (GC) B cells in their spleens when immunized with T-cell-dependent antigen. The increased numbers of T(fh) and GC B cells in Taci(-/-) mice are largely a result of up-regulation of inducible costimulator (ICOS) ligand on TACI-deficient B cells, given that ablation of one copy of the Icosl allele restores normal levels of T(fh) and GC B cells in Taci(-/-) mice. Interestingly, despite the presence of increased T(fh) and antigen-specific B cells, immunized Taci(-/-) mice demonstrate defective antigen-specific antibody responses resulting from significantly reduced numbers of antibody-secreting cells (ASCs). This effect is attributed to the failure to down-regulate the proapoptotic molecule BIM in Taci(-/-) plasma cells. Ablation of BIM could rescue ASC formation in Taci(-/-) mice, suggesting that TACI is more important for the survival of plasma cells than for the differentiation of these cells. Thus, our data reveal dual roles for TACI in B-cell terminal differentiation. On one hand, TACI modulates ICOS ligand expression and thereby limits the size of T(fh) and GC B-cell compartments and prevents autoimmunity. On the other hand, it regulates the survival of ASCs and plays an important role in humoral immunity.

Citation

Xijun Ou, Shengli Xu, Kong-Peng Lam. Deficiency in TNFRSF13B (TACI) expands T-follicular helper and germinal center B cells via increased ICOS-ligand expression but impairs plasma cell survival. Proceedings of the National Academy of Sciences of the United States of America. 2012 Sep 18;109(38):15401-6