B cell activating factor of the TNF family (BAFF, also known as BLyS) promotes B cell survival and activation by binding distinct B cell surface receptors, namely BAFF receptor (BAFF-R) and Transmembrane activator and CAML interactor (TACI). Although increased BAFF levels have been implicated in the pathogenesis of SLE, how excess BAFF promotes breaks in B cell tolerance is not completely understood. Since BAFF-R deletion results in loss of mature B cells, BAFF-R-dependent signals were presumed to explain BAFF-mediated autoimmunity. However, we made the surprising observation that B cell TACI signals are critical for BAFF-driven autoantibody production.

Methods:

To test the requirement for B cell receptor (BCR) and Toll-like receptor (TLR) signals in TACI-dependent autoantibody production, we crossed Btk^-/-, Myd88^-/-, Tlr7^-/- and Taci^-/-strains with transgenic mice over-expressing BAFF (BAFF-Tg).

Results:

Despite prior studies suggesting that TACI signals negatively regulate B cell activation, we observed that TACI deletion results in a striking loss of class-switched autoantibodies and protection from immune-complex glomerulonephritis in BAFF-Tg mice. Importantly, lack of autoimmunity was not explained by alterations in peripheral B cell development, since both BAFF-Tg and Taci^-/-.BAFF-Tg mice exhibited similar B cell hyperplasia. Rather, whereas surface TACI expression is usually limited to mature B cells, we discovered that excess BAFF promotes increased TACI by an activated subset of developing transitional B cells. This novel TACI^hi transitional population exhibits an activated, cycling phenotype, is enriched for autoreactive BCR specificities and directly contributes to class-switched autoantibody formation in BAFF-Tg mice. To dissect the B cell-intrinsic signals required for transitional B cell TACI expression and autoantibody production, we crossed BAFF-Tg animals with mice deficient in the B cell signalling adaptor Bruton’s tyrosine kinase (Btk). Notably, Btk^-/-.BAFF-Tg exhibited abrogated serum autoantibodies which correlated with loss of surface TACI on transitional B cells. In contrast, despite previous studies reporting a requirement for B cell-intrinsic TLR signals in BAFF-driven autoimmunity, deletion of either the TLR adaptor Myd88 or the endosomal RNA receptor TLR7 exerted no impact on transitional TACI expression. Rather, deletion B cell TLR signals exerted an isolated impact on transitional B cell class-switch recombination, without impacting BCR-dependent TACI upregulation; findings identifying distinct contributions of BCR and TLR signalling pathways to BAFF-driven autoantibody production.

Conclusion:

Our combined findings advance our understanding of how integrated B cell signals promote humoral autoimmunity, by highlighting a novel mechanism in which increased BAFF drives TACI-dependent activation of developing transitional B cells. In addition to informing the genesis of SLE, these findings are likely of particular relevance to the understanding of disease relapse after B cell-depletion with Rituximab; a state characterized by B cell reconstitution within a high BAFF environment.