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

Abstract

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 antigenspecific 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.costimulation | T-cell-dependent humoral immunity | TNF receptor T ransmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI/TNFRSF13B), B-cell activating factor (BAFF) receptor (BAFF-R/TNFRSF13C), and B-cell maturation antigen (BCMA/TNFRSF17) are closely related members of the TNF receptor superfamily and bind B-cell survival cytokines BAFF and APRIL (1). Although BAFF-R and BCMA have been shown to mediate the survival of follicular B cells (2) and plasma cells (3), respectively, a similar role for TACI in mediating the survival of B lymphocytes at any particular stage of B-cell differentiation has not been demonstrated definitively.However, mutations in TACI are thought to contribute to ∼10% of common variable immunodeficiency (CVID) in humans (4, 5). This syndrome is characterized by antibody deficiency in late childhood and early adulthood. Paradoxically, some patients with TACI-mutated CVID also develop autoimmune diseases (6). How TACI deficiency leads to antibody deficiencies on one hand and autoimmunity on the other hand is not well understood.Mice lacking TACI have been generated (7,8), and initial characterizations of these mice revealed modest phenotypes. Taci −/− mice had increased numbers of B cells but exhibited decreased antibody respons...

CVID-associated TACI mutations affect autoreactive B cell selection and activation

“…In agreement with this hypothesis, murine models have demonstrated that either CD86 or ICOSL deficiency abolish GC formation and impair the generation of Tfh cells (50)(51)(52). However, expanded Tfh cells driven by overexpression of ICOSL on B cells have been reported in Taci knockout mice (53). Such differences between mouse and man may reconcile KREC assay.…”

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

“…ICOSL/ICOS costimulatory signals at the time of DC priming are critical for T FH cell development (25-27, 38, 54). Furthermore, the degree of ICOSL/ICOS engagement has been shown to determine the size of the T FH cell population (55) and to promote the localization of T FH cells within the GC (56). Importantly, mutation of a negative regulator of ICOS mRNA, Roquin, leads to autoimmunity that has been attributed to overly active T FH cells (57,58).…”

TACI deficiency enhances antibody avidity and clearance of an intestinal pathogen

“…TACI signaling causes sustained expression of BLIMP-1 (2), a transcription factor that orchestrates maturation of B cells into long-lived antibody-secreting cells (3,4) and inhibits apoptosis of plasma cells (5); however, the full spectrum of functions of TACI is not known. Deficiency of TACI in mice and humans causes Ig concentrations in blood to be low (hypogammaglobulinemia), impairs long-lived responses to encapsulated bacteria and influenza (6)(7)(8), and can predispose to various combinations of lymphoproliferation, tumor formation, and autoimmunity (9,10).…”