Advancing age increases one's vulnerability to certain diseases due in part to the diminishing immunocompetency which accompanies the aging process. The long-range goal of these studies is to identify the mechanisms underlying the age- associated changes in lymphocyte function, specifically focusing on Interleukin2 synthesis and function in the aged. This proposal is predicated on the finding that the synthesis of IL-2 is impaired in aged individuals, that this deficiency underlies the global reduction of immune responsiveness in mice, and that several cell-mediated and humoral immune responses can be restored by the addition of IL-2. The proposed experimentation focuses on three specific aspects of the function of IL-2 in the aged mouse. Firstly, the consequences of administering IL-2 to aged animals will be examined, assessing the impact of IL-2 on several parameters of T cell maturation and determining the duration of the immunoreconstitution achieved by IL-2 supplementation. Secondly, a complete description of IL-2 receptor expression by aged lymphocytes will be obtained, determining the relative density of the high and low affinity subsets. Some effort will be directed toward increasing IL-2R display by aged cells, and thus determine mechanisms affecting expression of this receptor in the aged. The consequences of IL-2 binding to aged and young lymphocytes will be explored at the cellular and molecular level, examining the rate of cell cycle entry and progression, the dose response profile, and the activation of intracellular protein kinases. Finally, the synthesis and utilization of IL-2 by mucosal- associated T lymphocytes will be investigated. This is of particular interest as the gutassociated lymphoid tissue, in striking contrast to the sensitivity of splenic lymphocytes, appears resistant to the deleterious effects of aging. Thus, a comparison of these two tissues can identify which age-associated cellular and molecular changes are responsible for the loss of immune reactivity. It is hoped that the results might eventuyally lead to the design of therapies to restore immune function in the elderly, enhancing the quality of life through better health, and may further apply to other disease conditions in which lymphokine synthesis or activity is impaired.
