Nitric Oxide Regulates BAFF Expression and T Cell–Independent Antibody Responses

Abstract

Whereas NO is known to regulate T cell responses, its role in regulating B cell responses remains unclear. Previous studies suggested that inducible NO synthase 2 (NOS2/iNOS) is required for normal IgA Ab responses but inhibits antiviral IgG2a Ab responses. In this study we used NOS2−/− mice to determine the role of NO in T cell–dependent and T cell–independent (TI)-2 Ab responses. Whereas T cell–dependent Ab responses were only modestly increased in NOS2−/− mice, IgM and IgG3 Ab responses as well as marginal zone B cell plasma cell numbers and peritoneal B1b B cells were significantly elevated after immunization with the TI-2 Ag 4-hydroxy-3-nitrophenyl acetyl (NP)–Ficoll. The elevated TI-2 responses in NOS2−/− mice were accompanied by significant increases in serum levels of BAFF/BLyS and by increases in BAFF-producing Ly6Chi inflammatory monocytes and monocyte-derived dendritic cells (DCs), suggesting that NO normally inhibits BAFF expression. Indeed, we found that NOS2−/− DCs produced more BAFF than did wild-type DCs, and addition of a NO donor to NOS2−/− DCs reduced BAFF production. Bone marrow chimeric mice that lack NOS2 in either nonhematopoietic or hematopoietic cells had intermediate IgM and IgG3 Ab responses after NP-Ficoll immunization, suggesting that NOS2 from both hematopoietic and nonhematopoietic sources regulates TI-2 Ab responses. Similar to NOS2−/− mice, depletion of Ly6Chi inflammatory monocytes and monocyte-derived DCs enhanced NP-specific IgM and IgG3 responses to NP-Ficoll. Thus, NO produced by inflammatory monocytes and their derivative DC subsets plays an important role in regulating BAFF production and TI-2 Ab responses.