Crucial role for TACI in TLR activation and macrophage phenotype determination (P1206)

Abstract

Abstract Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) regulates antibody responses to T cell independent type 2 (TI-2) antigens such as polysaccharides. However, it is not known whether TACI is important in generation of Ab response against T cell dependent (TD) antigens. In this study, we investigated the role of TACI in Ab responses against Neisseria meningitidis type C polysaccharide-tetanus toxoid conjugate (MCPS-TT) vaccine. We found that TACI-/- mice had lower amounts of Abs against MCPS and TT compared to WT mice. More importantly, even the potent adjuvant CpG did not augment Ab responses to MCPS-TT vaccine in TACI-/- mice. Stimulation of splenic cells or peritoneal macrophages of TACI-/- mice with CpG, LPS, or PolyI:C led to a significantly impaired production of pro-inflammatory cytokines and lower levels of co-stimulatory molecule upregulation, suggesting that TACI plays a key role in TLR signaling. Significantly lower expression of TLR9, TLR4, TLR3 and CD14 as well as impaired co-localization of the adaptor molecules, MyD88 and TRIF with the TLR receptors is likely to play a role in the impaired TLR response in TACI-/- mice. Further characterization of TACI-/- macrophages revealed that they manifest the characteristics of alternatively activated (M2) macrophages. Thus, M2 macrophage phenotype appears to be responsible for the impaired TLR activation and poor Ab responses to TD antigens in TACI-/- mice.