Signals that result from thymocyte-stromal cell interactions and locally produced cytokines and hormones play a central role in the generation and maintenance of a competent immune system. These signals modulate very specific and highly regulated phases of proliferation and differentiation of thymocytes. Several nuclear factors, NF-kappaB, AP-1 and NF-AT, and p38 MAP kinase are induced in thymocytes by intrathymic signals. These signals regulate normal T cell development and are essential for Thymocyte survival. For example, glucocorticoids target immature thymocytes by down regulating intrathymically induced NF-kappaB and AP-1 in vivo. Ectopic induction of Ras in the thymus of mice expressing transgenic activated Ras also disregulates intrathymically activated signals and causes tumors. These observations suggest that appropriate intrathymic signals are needed for survival and differentiation of thymocytes and disruption of these signals by glucocorticoids or by activated Ras result in cell death or in tumorigenesis. Experiments described in this application are aimed at defining the role of the inducible nuclear factors and p38 MAP kinase activity in normal thymocyte survival and development.
The specific aims are: i. to block p38 MAP kinase activity and assess the effect on T cell maturation; ii. to generate and analyze transgenic mice expressing dominant negative forms of upstream regulators of p38 MAP kinase to determine the role of this enzyme in the survival and/or development of T cells; and iii. to further define and clone a novel thymus specific """"""""AP-1 binding"""""""" protein whose DNA binding activity is negatively regulated by dexamethasone treatment of thymocytes and by activated Ras in the thymus. Long term goals are to define that support survival of immature thymocytes and modulate T cell development. A clear knowledge of the nature of intrathymic signals will provide insight and molecular tools needed to understand T cell tumors of the thymus and to combat immunodeficiencies from genetic defects and from diseases such as AIDS.
