Critical Need Beyond T Cell Help
Co-stimulation_Model

ABBREVIATIONS: FDC, Follicular dendritic cells; Ag, antigen; IC, immune complexes; ICCOSOME, immune complex coated bodies; BCR, B cell receptor; CD21L, CD21 ligand, TCR, T cell receptor; Ag-pept, processed antigen on MHC class II.


SUMMARY: The necessity of T cell help for B cell responses is well known. At the molecular level, interactions between TCR and peptide (derived from processed ICCOSOM-al Ag) on MHC class II as well as CD40-CD40L, are critical. In addition to T cell-B cell interactions, we believe there is a need for FDC-B cell interactions for induction of optimal antibody responses and these interactions provide Ag for BCR and a CD21L to stimulate the B cell-CD21/CD19/TAPA-1 complex. IC form as soon as Ab is produced in primary responses and immediately upon challenge in recall responses. However, IC are poorly immunogenic in vitro and interaction of IC with B cells causes co-ligation of BCR and Fc receptors and elicits an inhibitory signal. Interestingly, some IC are trapped on FDC and subsequently germinal centers form, somatic mutations occur, high affinity antibody is produced and memory B cells are generated.

These data prompted the hypothesis that FDC regulate the immunogenicity of IC and provide critical signals to B lymphocytes beyond those provided by T cells. Addition of IC to specific T and B cells in culture fails to elict antibody responses. In contrast, the addition of FDC to cultures containing memory B & T cells and IC results in dramatic antibody responses. However, FDCs derived from FcgRIIB-/- mice support only low-level antibody production implicating FcgRIIB in handling IC. Interestingly, blockade of the CD21/CD19/TAPA-1 complex on the B cell or CD21L on FDC dramatically reduced antibody responses (10-100,000 fold reductions). Moreover, FDC from C3 knockout mice, which cannot generate the CD21L, are unable to provide the cosignal. In short, complement activating IC on FcgRIIB+/+ FDC provides both antigen and FDC-CD21L to signal BCR and B cell-CD21. Thus, induction of optimal specific recall responses appears to require "help" from both T cells and FDC.
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