Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling

Abstract

Using mice double deficient for tumor necrosis factor (TNF) and lymphotoxin alpha (LTα), we demonstrated that TNF and/or LTα are necessary for development of a normal splenic microarchitecture and for isotype switch after immunization with sheep red blood cell (SRBC). In the present study, we extended these observations by determining which TNF receptor (TNFR) is involved in morphological and functional differentiation of the spleen. Spleen morphology and antibody response were investigate in wild-type, TNFR1(-/-), TNFR2(-/-), and TNF/Ltα(-/-) mice immunized with SRBC. TNF/LTα(-/-) mice, which have a complete disruption of the TNF/LTα signaling system including the LT̄ receptor pathway, displayed an abnormal microarchitecture, and isotype switch did not take place. TNFR1(-/-) and TNFR2(-/-) mice displayed a normal spleen microarchitecture and mounted and IgM and IgG antibody response to SRBC. However, the IgG production in TNFR1(- /-) mice was minimal, with titers leveling off 6 d after immunization. In this strain, immunofluorescence revealed a lack of follicular dendritic cells (FDC) network, detected with FDC-M1 as well as anti-CR1, and a lack of germinal centers, detected with peanut agglutinin. In conclusion, whereas normal splenic microarchitecture and isotype switch might required the LTβ receptor, differentiation of FDC network, development of germinal centers, and full IgG response depend on signaling via TNFR1.