Our previous studies of T lymphocyte function in aging mice, using limiting dilution analyses (LSA), have suggested that a loss of antigen- and mitogen-reactive precursor cells for both helper and cytotoxic function may be an important component of age-associated immune dysfunction. We now propose to test the importance of precursor cell number for immune function by studies of mice in which the usual relationship between immune status and chronologic age has been altered by food restriction, parabiosis, or chimerism. Since the LDA technique permits repetitive, nondestructive testing of immune status using extremely small (5-50 ul) samples of peripheral blood, we will be able to use longitudinal designs to describe the time course of immune cell loss in normal and experimental mice. We also plan to use LDA techniques to study, at the clonal level, age-related changes in the production of memory T helper cells, and in the patterns of effector function -- e.g. lymphokine secretion and promotion of antibody synthesis -- generated by individual helper T cell precursors. Related methods will also allow us to classify precursor cells according to their fine specificity (in reactions to influenza virus), and in reactions to suboptimal stimulation at low antigen concentrations or in the presence of a limiting dose of blocking antibodies, e.g. L3T4. We plan as well to examine the kinetics and functional implications of IL-2 receptor expression in T cells from donors of different ages. Lastly, we plan to carry out pilot studies of age-related changes in T precursor cell number and subset distribution in humans. We hope that this research program will generate a coherent and detailed model of the cellular changes which underlie the age-associated decline in T cell immune function.
Showing the most recent 10 out of 43 publications
