In the periphery, an encounter with a foreign antigen stimulates lymphocyte activation and the generation of immunologic memory. Some cells that are in the periphery can recognize self-antigen and the development of immunologic memory must be prevented. The proposed study will attempt to elucidate the relationship between tolerance and memory development. This research application is based upon the described observation that memory T-cells are selectively tolerized to superantigens. In addition, the data suggest that there are differences between virgin and memory T-cells in their antigen recognition and signalling processes. The current study will characterize these differences using an animal model with which to study memory T-cell tolerance. T-cell receptor transgenic mice will be used to examine the processes underlying the responses to conventional antigens and superantigens, as the transgenic T-cell receptor recognized both peptide and superantigen.
The specific aims of the study are 1) to determine the fate of cells subjected to superantigen-mediated tolerance. This would be approached by using flow cytometry to examine whether superantigens induce apoptosis or halt memory cells at a certain point in the cell cycle; 2) to discern differences in the signalling processes between virgin and memory T ells in response to a) conventional antigens and b) superantigens. This study will address signalling processes biochemically by looking at protein kinase C activation and intracellular calcium fluxes. Costimulatory signals that will induce or break tolerance in virgin and memory T-cells will also be examined. This will include the examination of possible co-factors such as stimulatory signals; 3) to determine the effect of tolerance on memory T-cell subset. These experiments will examine the roles of cytokines in maintaining or breaking tolerance and in modulating T-cell function. The studies will also determine whether normal TH1 and TH2 TM cell subsets are equally susceptible to superantigen-mediated tolerance. Previous studies have focussed on preventing disease onset by tolerizing potentially reactive virgin T-cells. One hypothesis that might be made from the aforementioned model would be that an ongoing autoimmune disease might be ameliorated by the induction of tolerance in autoimmune memory T-cells. The long-term goal of this research project will be to apply the results gained from the completion of these studies to therapies for autoimmune disease.
| Watson, Andrew R O; Janik, David K; Lee, William T (2012) Superantigen-induced CD4 memory T cell anergy. I. Staphylococcal enterotoxin B induces Fyn-mediated negative signaling. Cell Immunol 276:16-25 |
| Lee, William T; Prasad, Aparna; Watson, Andrew R O (2012) Anergy in CD4 memory T lymphocytes. II. Abrogation of TCR-induced formation of membrane signaling complexes. Cell Immunol 276:26-34 |
