Roles for TACI, a BLyS receptor, in toll-like receptor stimulated B cells and marginal zone fitness

The BLyS family of receptors and ligands plays a pivotal role in B cell survival and differentiation. This family includes two cytokines, BLyS and APRIL, and three receptors: BLyS receptor 3 (BR3), transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA). Each receptor plays a different role in homeostatic control. TACI was originally described as a negative regulator of B cell survival. TACI expression varies within and among naive and activated cells. Compared to naive follicular (FO) cells, plasmablasts generated by T dependent and T independent type 2 responses and marginal zone (MZ) B cells express higher levels of TACI. Therefore, I examined the role of TACI in TLR-activated and naive B cells. Either TLR4 or TLR9 stimulation increases overall BLyS binding because of a preferential increase in TACI expression. Both TLRs depend upon MyD88-dependent signaling but with different subsets of cells responding. Both FO and MZ B cells all respond to TLR9 stimulation; while MZ B cells also respond in unison to TLR4, only a minority of FO B cells do so. Both BLyS and APRIL improve the survival of resting and BCR stimulated B cells; however, only BLyS enhanced viability of TLR stimulated cells. While these results suggested a role for TACI in activated cells, a different system was needed to examine naive B cell homeostasis. Therefore, I generated mixed marrow chimeras from wild-type (WT) and TACT-/- (KO) donors. Mice lacking TACI have normal bone marrow, increased cell numbers in all peripheral B cell compartments, and elevated serum BLyS concentrations, in agreement with previous reports. In mixed marrow chimeras, the bone marrow B cells appeared normal in number and composition and most compartments reconstituted with normal contributions from WT and KO marrow. However, the MZ showed a progressively reduced contribution from KO marrow despite elevated serum BLyS levels. When anti-BLyS was used to reduce serum BLyS concentrations in a cohort of chimeras, recirculating B cells reconstituted with undisturbed proportions of WT and KO cells. These findings demonstrate that TACI plays a role in both TLR-activated B cells and MZ fitness.