Cellular and molecular studies of marginal zone B cells

Abstract

Marginal zone (MZ) B cells are the major cell population in the spleen to respond to T-independent type II antigens (Ti-II) in the blood. However, the evidence regarding the potential role of MZ B cells in response to T-dependent Ag (Td-Ag) is still rudimentary and somewhat controversial, as studies with Pyk-2-/- and RBP-J conditional deficient mice showed opposite results. The current study compared in detail, the responses of MZ and follicular (FO) B cell to a Td Ag, Nitrophenyl-hapten (NP) coupled to chicken gamma globulin (NP-CGG) in an adoptive transfer experiment. The results showed that MZ B cells are the major population to generate early antibody-forming cells (AFC) and they produce about 10-fold higher IgM and slightly higher IgG throughout the entire primary response observed (3 months) compared to FO B cells. In addition, MZ B cells gave rise to germinal center (GC) formation albeit with a delayed onset. GCs from both MZ and FO B cells displayed similar levels of somatic hypermutation (SHM) frequencies, clonal selection, and IgG memory responses. Surprisingly, MZ B cells also produced an IgM memory response. The VH gene repertoire of the early antibody forming cells (AFCs) from MZ B cells is different from that of GCs and late AFCs, suggesting their origins from different precursors. Studies on gene expression profile showed that MZ B cells express some early activation markers both on cell surface, such as B7-2, CD54, and CD44, and intracellularly, such as c-myc, pim-1, and fos proteins, consistent with their rapid response to stimulation. Most importantly, MZ B cells upregulate gene expression of the Blimp-1, which confers MZ B cells the propensity to rapidly develop into plasma cells. In addition, MZ B cells differentially express higher levels of RP105, a LPS receptor on B cells, which may explain the stronger response of MZ B cells to LPS stimulation and the predominant role in Ti responses. In conclusion, MZ B cells are phenotypically and functionally heterogeneous and they have the potential to respond to both Ti and Td Ags.