Cancro, Michael P.

Abstract Respiratory infection with influenza virus (flu) induces long-lasting protective humoral immunity. Although flu-specific antibody secreting cells (ASCs) increase post infection (p.i.) and are present in various organs, including the lung, it is unclear what signals promote their maintenance and/or survival. We determined that flu-specific ASCs were maintained in the lung up to half a year p.i.. These cells were not proliferating as they failed to incorporate BrDU. With the hypothesis that BLyS-family members may be important for ASC maintenance, we investigated the B cell response to flu in TACI-/- mice. TACI has been implicated in the T-independent type II response, but its role in anti-viral immunity is unknown. WT and TACI-/- mice exhibited a similar anti-flu B cell response at day 8 p.i., however, by day 33p.i., TACI-/- mice had significantly lower anti-flu antibody levels in the serum and locally in the lung. TACI deficiency did not affect flu-specific ASC numbers in spleen and lung-draining mediastinal lymph nodes. In contrast, it resulted in drastically reduced ASCs in lung and bone marrow. The results of our study will be discussed in the context of protection and possible implications for vaccine development.

Abstract Through their differential interactions with B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), the three BLyS family receptors play central roles in B cell survival and differentiation. Recent evidence indicates BLyS receptor levels shift following BCR ligation, suggesting that activation cues can alter overall BLyS receptor profiles and thus ligand sensitivity. In this study, we show that TLR stimuli also alter BLyS receptor expression, but in contrast to BCR ligation, TLR9 and TLR4 signals, preferentially increase transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) expression. Although both of these TLRs act through MyD88-dependent mechanisms to increase TACI expression, they differ in terms of their downstream mediators and the B cell subset affected. Surprisingly, only TLR4 relies on c-Rel and p50 to augment TACI expression, whereas TLR9 does not. Furthermore, although all follicular and marginal zone B cells up-regulate TACI in response to TLR9 stimulation, only marginal zone B cells and a subset of follicular B cells respond to TLR4. Finally, we find that both BLyS and APRIL enhance viability among quiescent and BCR-stimulated B cells. However, although BLyS enhances viability among TLR stimulated B cells, APRIL does not, suggesting that TACI but not BLyS receptor 3 may share survival promoting pathways with TLRs.