mTOR intersects antibody-inducing signals from TACI in marginal zone B cells

Abstract

Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI–mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.

BAFF inhibition in SLE—Is tolerance restored?

“…Functionally, BAFF upregulates Toll-like receptor (TLR) expression in B cells, and cooperates with dual BCR/TLR signals to drive T-independent B cell differentiation. [51][52][53][54] In addition, whereas combined BCR/TLR9 signaling induces B cell proliferation followed by apoptotic cell death, the provision of excess BAFF allows these cells to differentiate into short-lived plasma cells with pathogenic potential. 49,50 As described below, humoral autoimmunity in BAFF transgenic (BAFF-Tg) mice is T cell independent but requires signals through the TLR adapter molecule MyD88 and TACI, confirming the relevance of this crosstalk in driving breaks in B cell tolerance.…”

“…[51][52][53][54] In addition, whereas combined BCR/TLR9 signaling induces B cell proliferation followed by apoptotic cell death, the provision of excess BAFF allows these cells to differentiate into short-lived plasma cells with pathogenic potential. 52 These interactions have important implications for autoimmunity because cross talk between type 1 IFN, TLR, BCR, and BAFF signaling preferentially supports the survival, class-switch recombination, and plasma cell 57 An additional function of BAFF may be to preferentially enhance the generation of IL10-producing regulatory cells, [58][59][60] however this effect appears to be lost in the setting of inflammation ( Figure 3). By enhancing the production of the short TACI isoform, TLR9 signals amplify this response.…”

“…54 Importantly, whereas TACI expression is critical for BAFF-driven autoimmunity, BAFF-R signals exerted complementary roles in facilitating breaks in B cells tolerance. Alternatively, BAFF-R and TACI ligation could enhance B cell TLR mediated signals 52 and thereby facilitate class-switched autoantibody production. 75 Although the mechanisms whereby BAFF-R and TACI signals integrate to break B cell tolerance have not been completely defined, we hypothesize that BAFF-R signals both facilitate the survival of low-affinity autoreactive transitional B cells and promote the expansion of autoreactive clones that have engaged self-antigen.…”

“…49,50 As described below, humoral autoimmunity in BAFF transgenic (BAFF-Tg) mice is T cell independent but requires signals through the TLR adapter molecule MyD88 and TACI, confirming the relevance of this crosstalk in driving breaks in B cell tolerance. [51][52][53][54] In addition, whereas combined BCR/TLR9 signaling induces B cell proliferation followed by apoptotic cell death, the provision of excess BAFF allows these cells to differentiate into short-lived plasma cells with pathogenic potential. 55 Finally, TACI, in particular the short human isoform, can enter endosomal compartments where it associates with the TLR adapter molecule MyD88 through a domain separate from the TLR TIR domain to mediate enhanced NFκB signals that drive plasma cell differentiation.…”

“…46 Marginal zone B cells express high levels of TACI and in these cells TLR9 and TACI recruit both MyD88 and mTOR to facilitate T-independent class switching and plasma cell differentiation. 52 These interactions have important implications for autoimmunity because cross talk between type 1 IFN, TLR, BCR, and BAFF signaling preferentially supports the survival, class- 57 An additional function of BAFF may be to preferentially enhance the generation of IL10-producing regulatory cells, [58][59][60] however this effect appears to be lost in the setting of inflammation ( Figure 3). 61 In addition to regulating B cell survival, serum BAFF levels modulate the relative autoreactivity of the naive B cell repertoire.…”