The long term objective of this proposal is to understand the physiological consequences of mature T cells contacting antigen in vivo. The proposal focusses on Mls antigens, a class of murine endogenous """"""""superantigens"""""""" encoded by mammary tumor proviral loci. During the current funding period, evidence has been obtained that strong in vivo immune responses to Mls-a-bearing cells are followed by the elimination of most of the responding T cells. One of the major aims of the current proposal is to determine how this occurs. Particular emphasis will be placed on assessing whether elimination is a reflection of overstimulation of T cells by antigen. Other possibilities to be considered include a) that antigen-activated effector T cells are intrinsically short-lived, and b) that activated T cells are destroyed by regulatory/suppressor cells. Various approaches, including a careful characterization of the T cells that escape elimination, will be used to assess these possibilities. Preliminary work suggests that T cell elimination is partly a reflection of cell death per se but is also a reflection of T cell migration to mucosal surfaces. Various experiments are proposed to examine the relative contribution of cell death vs. altered lymphocyte migration to T cell elimination from the lymphoid organs. The type of cell death - apoptosis vs. necrosis - and the influence of cytokines on cell death will be studied. A third major issue to be addressed is the relationship between the induction of T cell anergy vs. T cell elimination. This issue will be examined by defining which particular experimental conditions favor anergy vs. elimination. Here it will be important to examine the role of ligand density and persistence of antigen. Although all of these various studies on T cell tolerance will be centered around Mls antigens, parallel studies will be performed with TCR transgenic T cells responding to a conventional antigen, cytochrome-C. Finally, information will be sought on why Mls-a antigens can be presented by the CD8 subset of T cells, i.e. cells that lack detectable MHC class II molecules. An in vitro model has been developed to study this paradox. Since inappropriate regulation of mature T cell responses is instrumental in a variety of diseases, including malignancy and autoimmunity, defining the factors involved in this regulation is of utmost importance.
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