T-independent antibody responses to T-dependent antigens: a novel follicular dendritic cell-dependent activity.
Follicular dendritic cells (FDCs) periodically arrange membrane-bound immune complexes (ICs) of T-dependent Ags 200-500A 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-FcgammaRIIB 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.
El Shikh
Mohey Eldin M
ME
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
El Sayed
Rania M
RM
Szakal
Andras K
AK
Tew
John G
JG
D000818:Animals; D000936:Antigen-Antibody Complex / Q000008:administration & dosage / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D000955:Antigens, T-Independent / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D000936:Antigen-Antibody Complex; D000945:Antigens, Differentiation, T-Lymphocyte; D000955:Antigens, T-Independent; D053264:B-Cell Activating Factor; D007075:Immunoglobulin M; C505720:Tnfsf13b protein, mouse; D010047:Ovalbumin