CONTROL OF PERSISTENT ANTIBODY RESPONSE BY FC RECEPTORS

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Long-term persistence of antigen-specific antibody and the generation of highly specific memory B cells are well recognized features of the humoral immune response. The specialized microenvironment of the germinal center (GC) may be key to these pathways, in particular, the ability of the follicular dendritic cells (FDC) to retain immunogenic antigen in the form of immune complexes (ICs) for extended periods. It has been proposed that this form of antigen both drives the selection of high affinity B cell receptor somatic mutants during the primary immune response, and maintains the stability of the memory B cell compartment over extended periods thereafter. Mice deficient in the activation Fc receptors FcgammaRI and FcgammaRIII display dramatically enhanced IC deposition and retention on FDCs. However, this does not lead to perturbation of the primary immune response. In Aim 1, we propose to test the hypothesis that this enhanced IC deposition and retention on FDCs will result in elevated levels of persistent serum antibody, memory B cells, and antibody forming cells (AFCs) in the bone marrow. We will also determine whether retention of ICs on FDCs is stable to subsequent immunization with a second antigen, and whether the affinity of persistent serum antibody is lower when cognate antigen levels on FDC are higher. B cell activity during the generation and maintenance of memory may also be regulated by direct interaction of ICs with antigen specific B cells via the inhibitory FcR, FcgammaRIIB. Mice deficient in this FcR display elevated serum antibody and AFC levels after immunization, consistent with this idea and with past in vitro studies on the functioning of this FcR. However, since FcgammaRIIB is the most widely expressed FcR, found on many myeloid lineages and FDCs, this conclusion remains tentative. In Aim 2 we propose to test the hypothesis that the dysregulated expression of antibody production observed in FcgammaRIIB. deficient mice is due to absence of this FcR on B cells. Finally, recent data have shown that the mechanism of inhibition of BCR signaling upon BCR-FcgammaRIIB co-ligation is mediated by recruitment of the inositol polyphosphate phosphatase SHIP to the ITIM motif in the cytoplasmic tail of FcgammaRIIB. A mutant form of FcgammaRIIB with a Y-greater than F change in the ITIM motif, precluding the Y phosphorylation necessary for SHIP binding, does not mediate inhibition of BCR signaling in transfected cell lines. In Aim 3, we propose to test the hypothesis that the ITIM-SHIP pathway is the only FcgammaRIIB initiated pathway necessary for inhibition of B cell activity in vivo, using mice engineered to express the FcgammaRIIB Y-greater than F mutant in the B cell compartment.