The broad, long-term goal of this project is to gain a better understanding of the biological roles of tumor necrosis factor (TNF) and interleukin 6 (IL-6) in immune recognition and T cell activation. Our working hypothesis is that TNF and IL-6, produced by antigen-presenting macrophages/monocytes (Mphi) as a result of their activation in the process of immune recognition, play important regulatory roles in T cell activation and differentiation. Elucidation of these regulatory mechanisms will be important in control of various diseases associated with abnormal T cell functions. The first specific aim is to characterize the generation of TMF and IL-6 by Mphi in the process of antigen-specific immune recognition. Isolated Mphi have been shown to produce TNF and IL-6 mainly in response to Gram negative bacteria (LPS) and certain viruses. Interaction with T cells may represent a more physiological stimulus for the synthesis of these cytokines Mphi. Alloantigen-, PPD- and EBV-associated antigen-specific T cell recognition models will be established. Production of TNF, IL-6 and other cytokines will be assessed at both protein and mRNA levels, and the interactions among cytokines will be determined using specific monoclonal antibodies and antisense oligonucleotides. Mechanisms of TNF and IL-6 production by Mphi during antigen presentation will be examined, and special attention will be focused on the interaction of MHC antigens with CD4/CD8 molecules. The second specific aim is to establish the roles of TNF and IL-6 in T cell activation and differentiation. Roles of IL-6 in T cell recognition and the importance of TNF and IL-6 in T cell activation will be studied. The questions whether the actions of TNF and IL-6 on T cells involve CD3 and/or CD2 activation pathways and whether the actions are mediated by IL-1, IL-2, and IL-4 will be answered. Specific target T cell populations of the actions of TNF and IL-6 will be identified mainly by cell separation procedures. The significance of TNF and IL-6 in differentiation of T helper and T suppressor cells will also be evaluated.
