Antiviral B Cell Memory in the Absence of Mature Follicular Dendritic Cell Networks and Classical Germinal Centers in TNFR1−/− Mice

Abstract

TNFR1−/− mice have been shown to lack networks of mature follicular dendritic cells (FDCs) and they do not form germinal centers. With nonreplicating Ags, IgG titers were inefficiently induced and not maintained. In this study, the neutralizing Ab response and the establishment of B cell memory in TNFR1−/− mice after infection with vesicular stomatitis virus (VSV) were analyzed histologically and functionally. Immunization with VSV-derived protein Ags without adjuvant induced only IgM but no IgG Abs in TNFR1−/− mice, whereas VSV glycoprotein emulsified in CFA or IFA induced IgM and IgG responses that were short-lived and of moderate titer. However, infection with live VSV induced excellent neutralizing IgM and IgG responses in TNFR1−/− mice, and adoptively transferable B cell memory was generated and persisted for more than 300 days. In contrast, IgG levels and Ab-forming cells in the bone marrow declined within 300 days by 90–95% compared with controls. These findings suggest that 1) increased Ag dose and time of Ag availability can substitute for FDC-stored Ab-complexed Ag in the induction of efficient IgG responses in TNFR1−/− mice devoid of classical germinal centers; 2) the induction and maintenance of adoptively transferable B cell memory can occur in the absence of Ag bound to mature FDCs; and 3) the long-term maintenance of elevated IgG titers is largely dependent on FDC-associated persisting Ag. However, about 5–10% of the Ab production remained in the absence of detectable persisting Ag in TNFR1−/− mice, probably either due to immature FDCs being partially functional and/or due to long-lived plasma cells.

Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells

“…However, we did not identify morphological differences between splenic and mesenteric germinal centers, and the TNFR1 Ϫ/Ϫ line used here (26) did not show abnormal germinal center responses after infection with vesicular stomatitis virus (21).…”

“…Ten-micrometer frozen sections of spleens or lymph nodes were immunostained with the follicular dendritic cell marker FDC-M1 (clone 4C11), CD35 (8C12, PharMingen), peanut agglutinin (PNA), or the pan-B cell marker anti-CD45RO͞B220 (RA3-6B2, PharMingen) as previously described (21).…”

Unresponsiveness to Lymphoid-Mediated Signals at the Neonatal Follicular Dendritic Cell Precursor Level Contributes to Delayed Germinal Center Induction and Limitations of Neonatal Antibody Responses to T-Dependent Antigens

“…This may reflect Ag persistence, favored by the use of the Al(OH) 3 depot adjuvant, giving time for FDC to eventually appear and nucleate a GC reaction as late as 2 wk after immunization. Similarly, increased Ag dose and time of Ag availability have been shown to substitute for FDC-stored Ab-complexed Ags in the induction of IgG responses in TNFR1 Ϫ/Ϫ mice devoid of classical GC (55). It is also of interest to note that although the delayed and limited early life GC reaction significantly limits ASC differentiation and primary IgG responses, it is nevertheless sufficient to allow the generation of memory B cells (20) and the Ab avidity maturation of certain T-dependent protein Ags (56).…”

Marginal Zone Macrophages and Immune Responses Against Viruses

“…However, despite generating normal T and B cell responses, op Ϫ/Ϫ mice were susceptible to viral infection. This points to the importance of the architecture of lymphoid organs for controlling viral infections in vivo (42)(43)(44)(45). Crucial functions of structural components of lymphoid organs may not be uncovered if nonreplicating Ags are used.…”