Immune Complex-Bearing Follicular Dendritic Cells Deliver a Late Antigenic Signal That Promotes Somatic Hypermutation

Abstract

We reasoned that immune complex (IC)-bearing follicular dendritic cells (FDCs) promote somatic hypermutation (SHM). This hypothesis was tested in murine germinal center reactions induced in vitro by coculturing 6-day (4-hydroxy-3-nitrophenyl) acetyl-primed but unmutated λ+ B cells, chicken γ-globulin (CGG) memory T cells, FDCs, and ICs (anti-CGG plus NP-CGG). Mutations in primed λ+ B cells were obtained only when both FDCs and immunogen were present. FDCs alone promoted B cell survival and Ab production but there were no mutations without more immunogen. Moreover, the mutation rate was enhanced when FDCs were activated. Trapped ICs ranged from 200 to 500 Å apart on FDC membranes and this correlated with the periodicity known to optimally signal BCRs. FDCs are unique in their ability to retain ICs for months and a second signal mediated by FDC-ICs appeared to be needed a week or more after immunization by immunogen persisting on FDCs. However, the time needed to detect extensive SHM could be reduced to 7 days if ICs were injected together with memory T cells in vivo. In marked contrast, no mutations were apparent after 7 days in vivo if ICs were replaced by free Ag that would not load on FDCs until Ab was produced. The data suggest that specific Ab production leads to the following events: Ab encounters Ag and ICs are formed, ICs are trapped by FDCs, B cells are stimulated by periodically arranged Ag in ICs on FDCs, and this late antigenic signal promotes SHM.

Vaccine Adjuvant MF59 Promotes Retention of Unprocessed Antigen in Lymph Node Macrophage Compartments and Follicular Dendritic Cells

“…FDCs are critical for the induction of a complete humoral immune response, because these cells are required to capture IC-bound Ags and stimulate cognate B cells (9,10), leading to an increase of the Ag-specific memory B cell population and expansion of the Ab-secreting plasma cells (13)(14)(15). FDCs have also been shown to function as a reservoir of Ag for uptake by lymphonodal DCs (16).…”

“…In addition, it has been demonstrated that cognate B cells acquire a portion of the FDC membrane together with the Ag (9). B cell activation determines both the expansion of the Ag-specific memory B cell compartment and the formation of plasma cells (13)(14)(15). Thus, FDCs exert a primary role in the induction of a humoral immune response.…”

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

“…Ab persistence is mediated by long-lived plasma cells in the bone marrow (BM) and generation of Ab-secreting cells (AbSCs) from memory B cells (7). High-affinity memory B cells are selected in germinal centers (GCs) in lymphoid organs (8), mediated by follicular dendritic cells (FDCs) retaining immune complexes (ICs) through FcRs and complement receptors (9). Cells involved in the initial deposition of ICs on FDCs include marginal metallophilic macrophages (MMMs) in spleen and subcapsular sinus macrophages of lymph nodes that both express CD169/MOMA-1 (10,11).…”

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

“…The nonmobile FDCs remain in the GCs where their intertwining dendrites create extensive Ag retaining reticula (ARR) intimately in contact with numerous mobile B cells (5,6). In GCs, which are typically involved in refining humoral immunity to TD Ags, FDCs promote: B cell survival, Ig class switching, somatic hypermutation, selection of somatically mutated B cells with high-affinity receptors, affinity maturation, B memory production, and induction of secondary IgG and IgE responses (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”