BLyS Neutralization Ablates Primary But Not Memory B Cell Pools

The cytokine BLyS (B lymphocyte stimulator) interacts with three receptors – BR3, TACI, and BCMA – to regulate the composition and size of peripheral B cell pools. BLyS‐BR3 interactions govern the size and composition of primary B cell subsets by controlling the proportion of transitional (TR) B cells that complete differentiation and determining the lifespan of mature follicular (FO) and marginal zone (MZ) B cells. The role of BLyS family members in the regulation and maintenance of other subsets, particularly antigen‐experienced and memory B cells, remains unclear. Accordingly, we have directly interrogated the role of BLyS in a primary T‐independent and T‐dependent antigen response and the maintenance of memory B cells in vivo , using a neutralizing anti‐BLyS antibody. Mice injected with 200 μg of anti‐BLyS show profoundly reduced numbers of TR, FO, and MZ B cells within two weeks following treatment, as well as significantly reduced serum BLyS levels. Mice challenged with T‐dependent or T‐independent antigen at 30d post‐treatment with anti‐BLyS mount attenuated responses, compared to untreated mice. However, mice that had been immunized with NP‐CGG 8wk prior to anti‐BLyS treatment show no reduction in NP‐specific memory B cells. Further, upon antigen rechallenge, the expansion of NP‐specific memory B cells and serum anti‐NP antibody levels are similar to controls. Together, these findings indicate that memory B cells are largely independent of BLyS, and therefore occupy a separate homeostatic niche from primary B cells.