The long range goal of the proposed research is to gain a more complete understanding of the molecular basis of the specificity and function of helper T lymphocytes in the initiation and promotion of antibody responses. The proposed experiments are based on recent findings in this laboratory and others that the activation of T cells to soluble protein antigens requires the processing of the native antigen to release a peptide fragment containing the T cell antigenic determinant which is held on the surface of an antigen presenting cell where it is recognized by helper T cell in conjunction with Ia. Once stimulated by its antigenic peptide and Ia T cells secrete nonspecific growth and differentiation factors which can activate resting B cells. B cells are capable of functioning as antigen presenting cells and moreover, B cells which bind an antigen are far more efficient in presenting that antigen to T cells, maximally activating T cells at greatly reduced antigen concentrations as compared to B cells which cannot bind antigen. Thus, under limiting antigen concentrations such as may occur in vivo only antigen specific B cells may be capable of functioning as APC and attracting helper T cells to their surface where growth and differentiation factors are released, providing a mechanism by which nonspecific helper factors can be selectively delivered to antigen-specific B cells. This application represents a continuation of studies of the helper T cell response to the globular protein antigen, cytochrome c. It is intended to define (1) the specificity of T cells for protein antigens focusing on the structural features of proteins and peptides which allow them to function as T cell antigens. (2) the capacity of B cells to interact with helper T cells as antigen presenting cells and as potential targets of immunoregulatory phenomenon, and (3) the repercussion of the T cell's activation by antigen presented by B cells as compared to macrophages or dendritic cells with respect to the induction or prevention of tolerance, the activation of B cells to antibody secretion and the induction of memory B cell differentiation.