Functional Heterogeneity of Marginal Zone B Cells Revealed by Their Ability to Generate Both Early Antibody-forming Cells and Germinal Centers with Hypermutation and Memory in Response to a T-dependent Antigen

Abstract

Marginal zone (MZ) B cells play a major role in the first-line responses against blood-born T-independent bacterial antigens (TI), but the full scope of their immune functions is not known. Here we compare the responses of MZ and follicular (FO) B cells to a T-dependent antigen (TD), hapten–(4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken γ-globulin, in a cell transfer system. Consistent with the conventional paradigm, MZ B cells but not FO B cells rapidly generated the early burst of NP-specific antibody-forming cells (AFC), high levels of IgM Ab, and early IgG with relatively high affinity to NP. However, MZ B cells were also capable of forming germinal centers (GCs) albeit with a delay, compared with FO B cells. The early AFCs and the GCs originated from different MZ precursors, but the MZ- and FO-derived GCs were similar in VH gene repertoire, somatic mutation, and production of late AFC and IgG Ab. Surprisingly, the MZ but not the FO memory response included IgM Ab. We conclude that MZ B cells are heterogeneous, comprising cells for both early AFC response and GC/memory pathway against TD antigens.

Categorical selection of the antibody repertoire in splenic B cells

“…In contrast, based on surface phenotypic criteria, the MZ subset appears to be enriched for cells that exist in a semi-activated state. Although given the proper stimuli MZ can engage in T-dependent responses, a large proportion of this population includes cells that appear primed to respond to T cell-independent challenges, such as those provided by polysaccharides on the surface of encapsulated bacteria [21,25,26]. The question then arises whether correlations can be made between the enrichment for short, polar CDR-H3 in the marginal zone and either the likelihood of pre-activation, or an altered range of preferred epitopes, or both.…”

Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen

“…First, the responses take place in nonirradiated WT mice, thereby allowing the normal navigation of responding lymphocytes through intact secondary lymphoid structures. Importantly, this approach avoids the potential problems associated with the use of lymphopenic recipients such as scid/scid and rag-1 Ϫ/Ϫ mice to visualize donor B cells (9,31). Moreover, it means that the B cell-specific functions of candidate immunoregulatory molecules can be interrogated by using B cells from SW HEL Ig-Tg mice crossed onto different genetically manipulated backgrounds.…”

“…In an attempt to compare the relative abilities of Fo and MZ B cells to mount T cell-dependent (TD) responses in vivo, a recent study was performed in which purified Fo or MZ B cells were challenged with TD Ag following transfer into lymphocyte-deficient scid/scid mice (9). In this system, MZ B cells were the major source of primary Ab secreting cells (ASCs), formed germinal centers (GCs) albeit with delayed kinetics, and underwent somatic hypermutation (SHM).…”

TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses

“…B-1 cells reside mainly in the peritoneal and pleural cavities and can be further subdivided into B-1a (B220 low IgM high CD11b ϩ CD5 ϩ ) and B-1b cells (B220 low IgM high CD11b ϩ CD5 Ϫ ). B-2 cells are primarily located in secondary lymphoid organs and comprise two populations designated as follicular (FO) 4 B cells (B220 ϩ CD23 high CD21 low ) and marginal zone (MZ) B cells (B220 ϩ CD23 low CD21 high ), respectively (1). Due to their unique location near the marginal sinus, MZ B cells are considered critical determinants of host defense directed against encapsulated blood-borne bacterial Ags (2).…”

“…Due to their unique location near the marginal sinus, MZ B cells are considered critical determinants of host defense directed against encapsulated blood-borne bacterial Ags (2). Nevertheless, there is increasing evidence of a broader role for MZ B cells in both T-independent (TI) and T-dependent (TD) immune responses (3,4). It has recently been documented that B-1b cells are mostly responsible for the adaptive immune response to TI Ag and exert a memory function (5,6).…”