We propose to continue our investigation of the inductive events and suppressor T cell/T cell factor (Ts/TsF)-mediated regulation of delayed-type hypersensitivity (DTH) responses to 2,4-dinitrofluorobenzene (DNFB). As precise analysis of the induction and effector mechanisms of complex inductive and regulatory circuits is possible only via the use of cells and factors from cloned T cell lines and hybridomas, particular emphasis will be given to the isolation and characterization of clonal sources of regulatory Ts/TsF and clonal sources of potential targets of these regulatory cells. Studies on the inductive events of DTH will focus on further characterization, on both the population and clonal levels, of the hapten-specific, MHC Class II-restricted T cell subsets involved in this process [helper T cells for DTH (Thdh), proliferative T cells (Tprlf), and precursor DTH effector cells (pTDH)]. Studies on the inductive and effector events of antigen-specific Ts circuits induced by the intravenous injection of syngeneic DNP-modified spleen cells (DNP-SP) will focus on several areas. The role of L3T4+ Ts-inducer (Ts-i) cells in the Ts circuit will be probed using in vivo injection of monoclonal GK1.5 antibody (directed against the MHC Class II T cell receptor-associated L3T4a determinant) and by examining the suppressive mechanisms of our recently described L3T4+ Ts-i clones. The mechanisms and cellular targets of efferent (elicitation phase) and afferent (induction phase)-acting Ts-1 and Ts-2 effector cells will be investigated using both polyclonal and clonal sources of these cells and their targets. Lastly, major emphasis will be placed on investigation of the biochemistry, receptor genes, and molecular mechanisms of effector suppression using a monoclonal, DNP-specific, efferent-acting TsF (Clone 26.10.2) as a probe. Studies are proposed wherein genetic and molecular mechanisms of the divergent pathways by which this monoclonal TsF appears to mediate suppression will be examined - a) directly and specifically on DTH-effector TDH cells; b) indirectly via triggering of a nonspecific factor from antigen-primed Ts-auxiliary cells; and, c) via induction of second-order Ts. We feel that the past experience of our laboratory in the study of DTH immunoregulation and our recently developed technology for producing clonal sources of both DTH effector and Ts cells make these goals attainable. Understanding of Ts/TsF regulation of DTH responses gained by these studies should prove valuable for our future ability to manipulate the immune system for both the prevention and treatment of neoplasia and human immunoregulatory disease.
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