Our past research efforts on this grant have involved the functional analysis of murine Peyer's patch (PP) lymphoreticular cells and their contribution to induction and regulation of IgA responses. Oral T-dependent (TD) antigens induce T helper (Th) cells in PP which support IgA responses and clones of these Th cells have been obtained. These PP Th cells for IgA responses (PP Th A) bear Fc receptors for IgA (FcalphaR+) and preferentially collaborate with committed, surface IgA+ B cells via FcalphaR for preferential induction of IgA responses. T-T hybridomas derived from PP Th A cells are FcalphaR+ and secrete IgA immunoglobulin-binding factor(s) (IBFalpha) which support IgA responses. We will determine: 1) the activation stage of B cells required for PP Th A cell collaboration, 2) whether lymphokines other than IBFalpha are involved in B cell triggering, and 3) the molecular basis for IBFalpha-enhancement of the IgA immune response. To accomplish this, B cells at various stages will be tested with PP Th A cells and/or derived supernatants to determine the nature of B cells which function in IgA responses. T-T cell lines will be used to obtain IBFalpha for its purification and for determining its precise role in regulation (enhancement and suppression) of IgA responses. We have isolated functional PP dendritic cells (DC), which are I-A+, 33Dl+ and which support periodate-induced mitogenic and KLH antigen-specific T cell responses. In addition, new procedures have been developed for the purification of DC. PP DC activate T cells of the Lyt-1+ phenotype and these PP DC Lyt-1+ T cell mixtures induce polyclonal IgA responses, suggesting that a unique PP DC-T cell interaction is important for IgA responses, which helps explain why PP are a major IgA inductive site. We will determine the molecular basis for DC-T cell support of polyclonal IgA responses. Periodate-induced clusters will be used to isolate T cell clones, which preferentially induce B cells to IgA synthesis, and will allow a full characterization of T cells and lymphokines required for polyclonal IgA responses. Furthermore, we will extend our studies on the functional heterogeneity of DC populations by assessing differences in: 1) induction of B cell homing and 2) antigen presentation between the two DC types. These studies will be complemented by efforts to identify unique cell surface markers and to produce tissue-specific anti-DC antibodies for use as probes in the functional studies planned.
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