The immune system has evolved to neutralize pathogens, however, it must also dedicate much of its energy towards the avoidance of damaging the tissues whose job it is to defend. In the case of T lymphocytes, most potentially self-reactive cells are deleted during thymic development. T cells that recognize self-antigens not presented in the thymus will undergo maturation, however, and must be rendered tolerant (i.e., non-functional) in the periphery. Generally speaking, antigen-inexperienced (i.e., naive) T cells are primed to express effector/memory functions when they encounter cognate pathogen-derived antigens due to the presence of inflammatory (i.e., danger) signals. In contrast, when their cognate antigens derive from self, the lack of inflammation results in tolerance inducing signals. Interestingly, there might be physiological circumstances when T cells encounter cognate antigens expressed in both immunogenic and tolerogenic contexts. Thus, if recent thymic immigrants are specific to self, but are initially stimulated by a pathogen that expresses a cross-reactive epitope (i.e., molecular mimicry), they would likely develop effector functions and the potential to cause autoimmune pathology. If these effector T cells were susceptible to tolerization, the extent of ensuing autoimmune damage might be minimized. Additionally, the potential of effector T cells to be tolerized might also negatively impact T cell-based therapies to treat cancer since tumor antigens can be presented in a tolerogenic manner. We have recently shown that virally-primed CD4 cells can be induced to undergo tolerization when they encounter their cognate antigen expressed as a parenchymal self-antigen (even when expressed at low levels), via the same indirect antigen presentation pathway that induces na'ive CD4 cell tolerization. Interestingly, during this tolerization process the ability of virally-primed CD4 cells to express effector cytokines such as TNF-a and IFN-_ are lost more rapidly than their ability to express noneffector functions such as IL-2 production and proliferation. Furthermore, tolerization is mediated primarily through functional inactivation (rather than deletion), and is manifested in both lymphoid and non-lymphoid organs. This proposal will examine the cellular and molecular mechanisms that govern the regulation of this novel peripheral tolerization pathway. [unreadable] [unreadable]