Follicular dendritic cell (FDC)‐FcγRIIB engagement <i>via</i> immune complexes induces the activated FDC phenotype associated with secondary follicle development

Follicular dendritic cells (FDCs) periodically arrange membrane-bound immune complexes (ICs) of T-dependent Ags 200–500Å apart, and in addition to Ag, they provide B cells with costimulatory signals. This prompted the hypothesis that Ag in FDC-ICs can simultaneously cross-link multiple BCRs and induce T cell-independent (TI) B cell activation. TI responses are characterized by rapid IgM production. OVA-IC-bearing FDCs induced OVA-specific IgM in anti-Thy-1-pretreated nude mice and by purified murine and human B cells in vitro within just 48 h. Moreover, nude mice immunized with OVA-ICs exhibited well-developed GL-7+ germinal centers with IC-retaining FDC-reticula and Blimp-1+ plasmablasts within 48 h. In contrast, FDCs with unbound-OVA, which would have free access to BCRs, induced no germinal centers, plasmablasts, or IgM. Engagement of BCRs with rat-anti-mouse IgD (clone 11–26) does not activate B cells even when cross-linked. However, B cells were activated when anti-IgD-ICs, formed with Fc-specific rabbit anti-rat IgG, were loaded on FDCs. B cell activation was indicated by high phosphotyrosine levels in caps and patches, expression of GL-7 and Blimp-1, and B cell proliferation within 48 h after stimulation with IC-bearing FDCs. Moreover, anti-IgD-IC-loaded FDCs induced strong polyclonal IgM responses within 48 h. Blockade of FDC-FcγRIIB inhibited the ability of FDC-ICs to induce T-independent IgM responses. Similarly, neutralizing FDC-C4BP or -BAFF, to minimize these FDC-costimulatory signals, also inhibited this FDC-dependent IgM response. This is the first report of FDC-dependent but TI responses to T cell-dependent Ags.

Section: Blockade Of Fdc-fc␥riib -C4bp and -Baff Significantly Inhisupporting

confidence: 78%

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

Shikh

Sayed²,

Szakal³

et al. 2009

“…Thus, FDCs could be activated and ready to trap ICs and optimally stimulate B cells as soon as the first ICs are made. The ICs themselves can activate FDCs, but that requires 24 -48 h after encountering adequate amounts of ICs (44). The present study indicated that FDCs were activated via TLR4 engagement in 3 days, and that would precede Ab production and IC formation.…”

Section: Discussionmentioning

confidence: 54%

“…Up-regulating these adhesion molecules should promote FDC-B cell interactions, facilitate clustering and presentation of FDC-Ag to B cells, and enhance the GC reaction. The signaling pathway known to up-regulate FDC-ICAM-1 and FDC-VCAM-1 is mediated via the NF-B (43), and up-regulation of FDC-ICAM-1 and FDC-VCAM-1 may be initiated by ICs engaging FDC-Fc␥RIIB (44). Similarly, the NF-B pathway appeared to be activated when FDC-ICAM-1 and FDC-VCAM-1 were up-regulated by LPS, engaging FDC-TLR4 in the present study.…”

Section: Discussionmentioning

confidence: 99%

TLR4 on Follicular Dendritic Cells: An Activation Pathway That Promotes Accessory Activity

Shikh

Sayed

et al. 2007

Microbial molecular patterns engage TLRs and activate dendritic cells and other accessory cells. Follicular dendritic cells (FDCs) exist in resting and activated states, but are activated in germinal centers, where they provide accessory function. We reasoned that FDCs might express TLRs and that engagement might activate FDCs by up-regulating molecules important for accessory activity. To test this hypothesis, TLR4 expression on FDCs was studied in situ with immunohistochemistry, followed by flow cytometry and RT-PCR analysis. TLR4 was expressed on FDC reticula in situ, and flow cytometry indicated that TLR4 was expressed on surface membranes and TLR4 message was readily apparent in FDCs by RT-PCR. Injecting mice or treating purified FDCs with LPS up-regulated molecules important for accessory activity including, FDC-FcγRIIB, FDC-ICAM-1, and FDC-VCAM-1. Treatment of purified FDCs with LPS also induced intracellular phospho-IκB-α, indicating NF-κB activation, and that correlated with increased FcγRIIB, ICAM-1, and VCAM-1. FDCs in C3H/HeJ mice were not activated with LPS even when mice were reconstituted with C3H/HeN leukocytes, suggesting that engagement of FDC-TLR4 is necessary for activation. Moreover, activated FDCs exhibited increased accessory activity in anti-OVA recall responses in vitro, and the FDC number could be reduced 4-fold if they were activated. In short, we report expression of TLR4 on FDCs for the first time and that engagement of FDC-TLR4 activated NF-κB, up-regulated expression of molecules important in FDC accessory function, including FcγRIIB, ICAM-1, and VCAM-1, as well as FDC accessory activity in promoting recall IgG responses.

“…We first analyzed activation of FDCs in the LNs of mice immunized with PE in the presence or absence of MF59, 7 d after a secondary immunization, checking the expression of CD16/32, a described marker for FDC activation (7,32). The activation of FDCs was generally more evident after immunization with MF59, although it was also observed in the absence of adjuvant (Fig.…”

Section: Upon Immunizations With Mf59 Fdc Activation Is Associated Wmentioning

confidence: 99%

“…Follicular dendritic cells (FDCs) have been described to play a key role in the induction of B cell responses, particularly during reexposure of the immune system to a protein Ag (3)(4)(5)(6). FDCs capture circulating immune complexes (ICs) through the CR2 (CD21/35) and retain them for a long period (up to 3 wk) (3,5,(7)(8)(9). A prolonged exposure of the ICs on the FDC surface facilitates the encounter of the unprocessed Ag with cognate memory B cells (9,10).…”

mentioning

confidence: 99%

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

Cantisani

Pezzicoli

Cioncada

et al. 2015

Ag retention within lymph nodes (LNs) upon vaccination is critical for the development of adaptive immune responses, because it facilitates the encounter of the Ag with cognate lymphocytes. During a secondary exposure of the immune system to an Ag, immune complexes (ICs) that contain the unprocessed Ag are captured by subcapsular sinus macrophages and are transferred onto follicular dendritic cells, where they persist for weeks, facilitating Ag presentation to cognate memory B cells. The impact of adjuvants on Ag retention within the draining LNs is unknown. In this article, we provide the first evidence, to our knowledge, that the oil-in-water emulsion adjuvant MF59 localizes in subcapsular sinus and medullary macrophage compartments of mouse draining LNs, where it persists for at least 2 wk. In addition, we demonstrate that MF59 promotes accumulation of the unprocessed Ag within these LN compartments and facilitates the consequent deposition of the IC-trapped Ag onto activated follicular dendritic cells. These findings correlate with the ability of MF59 to boost germinal center generation and Ag-specific Ab titers. Our data suggest that the adjuvant effect of MF59 is, at least in part, due to an enhancement of IC-bound Ag retention within the LN and offer insights to improve the efficacy of new vaccine adjuvants.