This revised new application describes a research program on the immune functions of tumor necrosis factor (TNF). The main objective is to determine if TNF plays a role in T cell development, repertoire selection and T cell maintenance in the thymus and peripheral lymphoid tissues. The reasons for selecting TNF are fourfold: (1) In addition to its known lytic functions TNF has non-lytic immunological functions quite similar to IL-1. For example, the co-stimulatory activity for thymocyte proliferation is an activity shared only by TNF and IL-1, and not by other lytic molecules produced by T cells (such as lymphotoxin). (2) While IL-1 is produced by macrophages, TNF is produced by T, B and macrophages as either free of membrane-bound TNF. (3) Using monoclonal antibodies to TNF we defined two distinct domains in the TNF molecule involved in cell-kill and T cell co-stimulation. (4) We have found abundant TNF-producing cells with TNF mRNA in the normal thymus of young mice by in situ hybridization. One interesting aspect is that while cells with IL-1 mRNA are located only in the thymic medulla, the cells with TNF mRNA are located in medulla and also in the deep cortical regions of the thymus, both regions where repertoire and thymocyte subset selection take place. In sum, one of the key questions that we would like to answer is: What are TNF-producing cells doing in the thymus? Our hypothesis is that, although not being the sole mediator, TNF may be a key mediator of T cell differentiation and selection. It could participate in negative selection of improper T cells via its cytotoxic and cytostatic activities, and also mediate differentiation and positive selection via its IL-1-like non-lytic functions. The membrane-associated forms of TNF, depending on local triggering conditions, would favor localized and restricted participation of TNF, rather than systemic effects. These basic studies on the role of TNF in T cell development and maintenance in mice may determine if TNF could be included in the list of potential therapeutic immune-modulators for treatment of some immunological deficiencies.
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