Loss of TACI Causes Fatal Lymphoproliferation and Autoimmunity, Establishing TACI as an Inhibitory BLyS Receptor

Abstract

BLys , a key cytokine that sustains B cell maturation and tolerance, binds three receptors: BR3, BCMA, and TACI. Results from knockout mice implicate a major functional role for BR3 and a redundant one for BCMA in B cell function. TACI's role is controversial based on defects in TI antibody responses accompanied by B cell hyperplasia in knockout mice. We have presently characterized a precise role for TACI in vivo. TACI(-/-) mice develop fatal autoimmune glomerulonephritis, proteinurea, and elevated levels of circulating autoantibodies. Treatment of B cells with TACI agonistic antibodies inhibits proliferation in vitro and activation of a chimeric receptor containing the TACI intracellular domain induces apoptosis. These results demonstrate the critical requirement for TACI in regulating B cell homeostasis.

BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas‐mediated cell death

“…Accordingly, we found that APRIL, which signals through TACI but not through BAFF-R, does not promote Fas killing of LPS-activated B cells. Our data suggest that the model that TACI is a negative regulator of B cells, while BAFF-R is a positive regulator [39], may not always be the case since the effect of TACI or BAFF-R signaling depends on the context in which the B cell is signaled through these receptors. We also demonstrated that coupling of BAFF and LPS signaling induces an inhibition of the MEK/ERK pathway that may be responsible for Fas up-regulation.…”

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

“…Several TACI knockout, transgenic, and knock-in mouse models have been generated. Some of them develop lymphoproliferative disorders, splenomegaly, and severe SLE-like autoimmune disorders with premature death due to renal failure (34,35). These data from animal models suggest that in addition to its role in B cell activation, TACI plays an inhibitory role in lymphocyte homeostasis.…”

TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells

“…The other two receptors, transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag (BCMA), can bind both BLyS and a proliferation-inducing ligand (APRIL), and affinity measurements suggest that APRIL may be their physiologically relevant ligand. Mice lacking TACI have elevated B cell numbers (22,23), suggesting a potential negative regulatory role for this receptor, whereas BCMA appears to be involved in the control of plasmacytes, rather than mature resting B cells (24). In addition, TACI knockout mice display defective T cell-independent type II responses, further suggesting that TACI and BCMA may be involved in regulating the behavior of activated B cells.…”