Thymic involution is a gradual progressive process resulting in the disorganization of normal thymic architecture, coincident with a loss of thymocytes, and replacement of normal tissue with fat. Involution reduces both the endocrine function of the thymus and the ability of this organ to serve as the major site of T lymphocyte differentiation. It has been generally assumed that the effect of thymic involution on T cell differentiation is a global reduction in the number of cells moving through the developmental pathway. However, preliminary data presented in this proposal argues for a different hypothesis, that specific steps of the intrathymic T cell differentiation sequence are preferentially inhibited during involution. The data suggest that early steps in the developmental sequence are inhibited by the involution process resulting in an accumulation of CD4CD8 Pgp-1hi thymocytes. The first specific aim, is to test this hypothesis. Experiments are proposed which will assess the impact of thymic involution on the relative frequency of various thymocyte subsets and the rate of transition between different phenotypic populations which represent distinct intermediates in the developmental sequence. Changes intrinsic to the lymphoid compartment versus those intrinsic to the reticuloepithelial compartment will be distinguished. A particular focus will be the production and activity of cytokines, especially IL-7. The second specific aim of this proposal is to test the hypothesis that growth hormone and prolactin regulate intrathymic T cell maturation and thus are integral to the involution process. These pituitary hormones have been shown to be important regulators of thymic integrity and peripheral immune responses. The present proposal will establish their role(s) in postnatal T cell development, particularly in those steps shown in Aim -I to be affected during involution. The objectives of this proposal are to precisely define: the changes in intrathymic T cell differentiation occurring as a consequence of involution and the involvement of growth hormone and prolactin in the maintenance of normal thymopoiesis.
