Age related changes in molecular interactions between follicular dendritic cells and B cells during the germinal center reaction

Morphological and kinetic studies of immune complex (IC) trapping by follicular dendritic cells (FDCs) in vivo showed marked age-related deficits associated with the functional capacity and structural integrity of follicular dendritic cells (FDCs). To determine whether the age-related defect was the result of the aging of FDCs or change in the in vivo micro environment of FDCs (i.e., aging B and T cells), the FDC-B cell-T cell-Ag interaction was studied in an in vitro germinal center setting where various combinations of old and young cells could be compared. The hypothesis that aging reduces the accessory activity of FDCs was tested with increasing numbers of FDCs from young (12wks) or old (20mo) mice in the presence of young (12wks) B and T lymphocytes. The Ag specific stimulatory activity of FDCs was studied using the OVA-specific Ab response which was reduced by 40–50% in the presence of old FDCs. The expression of FDC-M1, CR1,2, FcγRIIB, and FDC-M2 epitopes, and PNA labeling of GCs was studied using immunohistochemistry. Labeling with FDC-M2 that reflects IC binding by FDCs was dramatically reduced in old mice and a reduction in B cell stimulation as indicated a dramatic reduction in PNA+ GCs were in agreement with the reduced presence of FcγRII on FDCs. We then further reasoned that a reduction in trapped ICs, which generate CD21 ligand (L) on FDCs, would lead to inadequate FDC-Ag-B cell interactions resulting in a depressed Ab responses. Consequently, we also examined the role of complement (C ′). Due to the inability to present the FDC-Ag and CD21L to B cells, the FDCs capacity to inhibit ITIM activation as indicated by SHIP phosphorylation, deteriorates in aged FDCs and this appears to explain the poor secondary Ab responses. However, incubation of the old FDCs with IC and C′ reverses the reduced co-stimulatory capacity of FDCs by providing CD21L for FDCs to present to B cells, the reversal of Ag-specific stimulatory activity of FDCs will have to depend on up-regulation of FDC FcγRII receptors. Future work will be directed toward understanding mechanisms involved in regulating FcγRII on FDCs with the goal of up-regulating FcγRII on old FDCs. We reason that up-regulation of FDC-FcγRII on old FDCs could restore potent high affinity Ab responses in the aged. (Abstract shortened by UMI.)...