Throughout development, maturation and activation, B cells are continuously exposed to two major opposing forces. The first is the drive to generate and maintain B cells with highly diverse immune receptors able to recognize the diversity of exogenous antigens. The second is the necessity to avoid damaging immune responses against self-components. The balance of these two forces ensures an inability to react to self-antigens while preserving defenses against pathogens. CD40-CD40L and BAFF-BAFFR cytokine pathways have been shown to play essential roles in B cell survival and differentiation. We investigated the regulatory mechanism of a novel adaptor molecule, termed Act1 in CD40 and BAFFR-mediated B cell survival. We found that CD40- and BAFF-mediated survival is significantly increased in Act1-deficient B cells. Consistent with this finding, Act1-deficient mice revealed a general increase in peripheral B cells, culminating in lymphadenopathy, splenomegaly, and the formation of autoantibodies. Act1 exerts its negative regulatory function in B cell survival through its direct impact on the immediate signaling events mediated by CD40 and BAFF. Act1-deficient B cells displayed enhanced CD40L- and BAFF-induced IkappaB phosphorylation and processing of NF-kappaB2(pl00/p52). Based on these findings, we hypothesize that Act1 is an important regulator for the homeostasis of B cells by attenuating CD40 and BAFFR signaling, modulating humoral immune responses. To test this hypothesis, we will first elucidate the mechanism by which Act1 negatively regulates the CD40- and BAFFR-mediated signaling (Specific Aim 1). We will then examine Investigate the physiological and pathological impact of the Act1-regulated pathways on B cell survival and humoral immune responses (Specific Aim 2). These proposed studies will provide us with the mechanistic insight for Act1's function, revealing how Act1 coordinately regulates CD40- and BAFFR-mediated pathways, thereby exerting its impact on B cell survival and modulating humoral immune responses. These findings will help us to elucidate the detailed regulatory mechanism for B cell homeostasis and opens new possibility to intervene the immune system.
