The major interface between the immune system and the external environment is at mucosal surfaces, particularly the intestinal mucosa. The major immunoglobulin isotype at mucosal surfaces is IgA, which is thought to play an important role in controlling microbial adherence and in limiting antigen absorption. Thus, the regulation of IgA responses is of great consequence; however, the induction and regulation of IgA responses to intestinal antigens is poorly understood. IgA is known to be quite T cell dependent and there is now good evidence for the existence of IgA-specific regulatory T cells. The role such T cells play in IgA responses as compared to non-isotype specific T cells, is unknown. Antigens in the intestine can result not only in IgA immunization, but also in a state of tolerance to subsequent immunization with that antigen. In many instances, this oral tolerance is due to the action of suppressor T cells elicited in gut associated lymphoid tissues (GALT). IgA immunization and oral tolerance have been thought to be independent processes occurring simultaneously. Our initial studies using protein antigens suggest instead the IgA immunization and oral tolerance are reciprocally linked, i.e., when one is present the other is absent. More systematic evaluation is needed to determine whether this relationship is due to shared or to independent suppressor mechanisms in GALT.
The specific aims of this proposal include: first, the delineation of the mucosal IgA response and oral tolerance to soluble protein antigens which are fed to mice, focusing particularly on lectins, which are able to bind to intestinal mucosa; and then to define the regulatory T cell pathways resulting in such responsiveness or tolerance. Second, to determine the T cell regulation of the mucosal and systemic immune response to a synthetic type 2 antigen, TNP-polyacrylamide. This antigen will serve as a simple model antigen of a type which is abundant in the intestine. Third, to define the importance of antigen form and function in elicitation of mucosal IgA responses, specifically the importance of binding to the intestine, of monomeric versus polymeric particulate forms of the antigen, and of various adjuvant molecules attached to or presented at the same time as antigen to GALT.
