Different partners in different places?

The BAFF family includes 2 ligands, BAFF and APRIL, as well as 3 receptors, BAFFr, TACI, and BCMA. These molecules are master regulators of B-cell survival and, because of their clear links to autoimmunity and neoplasia, have recently been the focus of intense investigation. In this issue of Blood, Bossen and colleagues reveal another of this family's secrets, showing that TACI, unlike BAFFr, requires oligomeric versions of BAFF or APRIL to support survival among plasmablasts and activated B cells. This finding not only solves lingering conundrums, but it also raises exciting possibilities about how this family diversifies its regulatory activities and, equally important, how it might be clinically manipulated.

Until now, the simultaneous expression of TACI and BAFFr among primary B cells has been perplexing. For example, despite the expression of both receptors, most primary B cells die quickly when faced with BAFFr mutations alone.¹  This lack of redundancy has been puzzling given that TACI signaling promotes survival and can bind both BAFF and APRIL. Further, TACI knockouts develop B-cell hyperplasia,²  implying a negative role for TACI—a similarly counterintuitive result given the survival-promoting effects of TACI signals. The current findings may explain both of these observations. Since the majority of soluble BAFF is trimeric, recirculating primary B cells will not receive positive signals via TACI, making BAFF-BAFFr interactions the sole determinant of their survival. Further, since TACI nonetheless binds the BAFF 3-mer, it may provide a neutral “sink” for the cytokine, possibly explaining B-cell hyperplasia in TACI knockouts, where BAFFr would not face competition from a sterile receptor. Alternatively, trimeric ligands might induce TACI signals that actively oppose downstream BAFFr signaling—a possibility that calls for further scrutiny.

The current findings also predict that oligomeric ligand forms will alleviate strict BAFF-BAFFr dependence. This idea bears directly on the growing literature suggesting APRIL-TACI interactions are important for activated B cells. Indeed, TACI up-regulation is a common feature of activated B cells,³  and APRIL is enriched in niches associated with sustained B-cell activity, such as the lamina propria and inflamed sites.⁴  Moreover, because APRIL can bind cell-surface proteoglycans,⁵  stromal elements affording such oligomeric tethering will yield microenvironments capable of enabling positive TACI signals. This potential for localized oligomeric forms underscores the crucial role played by shifts in B-cell trafficking and residency, since these will establish the likelihood of capturing oligomeric signals and thus dictate whether ongoing responses are curtailed or sustained.

This paper also marks the first demonstration of a system in which alternate forms of a soluble TNF ligand favor different receptor interactions and outcomes, providing a novel paradigm for expanding the possible results of ligand-receptor engagement and raising the question of whether this might extend to additional TNF receptor-ligand families.

Finally, exploiting these properties might afford precise targeting of certain B-cell populations. Such strategies might be particularly useful for enhancing the strength and duration of responses to vaccines or, conversely, for eradicating inflammation, autloimmunity, or neoplasia.