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

Abstract

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.

Lipopolysaccharide‐Induced In Vivo Activation of Follicular Dendritic Cells is Tumor Necrosis Factor Receptor‐1 Independent

“…This experiment showed that in normal mice after LPS injection, FDCs in vivo display clear morphological signs of activation in the lymphoid follicles as well as in the marginal zone, that is, enlargement of cells, increased thickness, length and number of cell prolongations. This finding is in line with the results of in vitro studies, which demonstrated that LPS induces the activation of FDCs (El Shikh et al, 2007). Furthermore, very recently, similar in vivo differentiation and activation of FDCs was reported after LPS in mouse lymph nodes (Garin et al, 2010).…”

“…Studies using genetargeted mice have shown that (lymphotoxin-b receptor signaling being provided) FDC development critically depends on the functional tumor necrosis factor receptor-1 (TNFR1) pathway: if this signaling route is disrupted, FDC clusters fail to develop (Le Hir et al, 1996;Liu and Banchereau, 1996;Pasparakis et al, 1996Pasparakis et al, , 1997Matsumoto et al, 1997aMatsumoto et al, , 1997b. Recently, it has been demonstrated that lipopolysaccharide (LPS) induces activation of FDCs in vitro (El Shikh et al, 2007). Whether this also occurs in vivo and what is the role of TNFR1 in this situation, however, remained uncertain.…”

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

“…In marked contrast, OVA-specific IgM was present in the sera of all IC-injected animals with or without adjuvant in just 48 h. The highest OVA-IgM levels were induced using OVA-ICs in adjuvant, and these IgM levels were maintained over a 7-wk assessment period. The adjuvant effect was expected, given that LPS activates FDCs and promote their accessory activity (33). Phenotypically normal heterozygous nu/ϩ mice also responded to ICs by producing OVA-specific IgM within 48 h (Fig.…”

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

“…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.…”