During the humoral immune response to T cell-dependent antigen, the combined processes of clonal selection and somatic hypermutation generate large clones of B cells that secrete abundant quantities of mutated antibodies. Recent studies from this laboratory have shown that antibody V regions are potentially immunogenic when viewed by the syngeneic T cell repertoire in the context of class II MHC molecules. This finding suggests that helper functions could be delivered to B cells through T cell recognition of antibody that is self-presented by the B cell. However, this would lead to a chronic state of unregulated antibody production. Therefore, we hypothesize that in the physiologic state tolerance is normally achieved to antibody V regions presented in the context of class II MHC structures. Experiments are proposed to test this hypothesis. Antibodies with well-defined V regions that are recurrently elicited in the immune response to a hapten will be tested as immunogenic substrates. T cell tolerance of these V regions in the context of class II MHC will be assessed in normal and transgenic mice that carry and express genes encoding mutated versions of these V regions known to be immunogenic. Tolerance will be assessed both before and after immune recruitment of B cells that synthesize the immunogenic V regions. The results of these experiments will advance our understanding of the role of T cell help in achieving specific humoral immunity without autoimmunity.
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