Follicular Antigen Binding Dendritic Cells

Virginia Commonwealth University, Richmond VA

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Abstract

[unreadable] DESCRIPTION (provided by the applicant): Effective humoral responses to T dependent Ags require not only T and B cells but also follicular dendritic cells (FDCs). Recent data indicate that FDCs can: 1- block apoptosis and promote the survival of specific B and T cells, 2- block the immunoreceptor tyrosine-based inhibition motif (ITIM) signaling in B cells, 3- promote B cell proliferation stimulated by antigen or mitogen, 4- promote production of IgM by virgin B cells and class switching to IgG, 5- promote the development of high affinity Ab, and 6- promote potent recall responses. It is essential that we know which FDC-molecules are critical for these accessory activities and understand how they are regulated. Preliminary data suggest that FDCs can lose important molecules and enter a "resting state" and that FDCs may be reactivated in germinal centers (GCs) where the molecules are re-expressed and function is restored. These observations prompt our hypothesis that FDCs exist in states varying from fully resting to fully activated and that differences in FDC phenotype are indicative of differences in FDC function. Furthermore, cells and cytokines in the GC microenvironment regulate FDC phenotype, state of activation, and function. FDC development and certain activation Ags appear to be B cell dependent. Expression of CD21L on FDCs and the Ag for FDC-M2 are complement dependent. Expression of FDC-CD23 appears to be T cell dependent and CD4OL likely interacts with FDC-CD4O and activates FDC in GCs. In the present application, we propose to define FDC activation in terms of critical molecules and elucidate the regulation of FDC activation. The specific aims are: 1. To determine whether FDC morphology and surface molecules (i.e., CD21, CD21L, CD23, CD32, CD35, CD4O, CD54, CD64, CD1O6, FDC-M1, FDC-M2 & IgG) can be regulated in vitro by manipulating GC B and T cells, immune complexes (ICs), complement, and cytokines. 2. To determine how the FDC phenotype relates to their accessory activity in promoting B cell activation, proliferation and survival. 3. To establish the need for FDCs in promoting in vitro primary responses and their subsequent maturation leading to production of high affinity IgG.