In both mice and humans, immune senescence is marked by reduced T cell diversity, owing, in part, to the presence of CD8 T cell clonal expansions (TCE). Recently, it was shown by our group that TCE affect the outcome of the immune response by producing """"""""holes"""""""" in T cell repertoire. Why and how are TCE generated, and what endows them with selective survival, growth and/or expansion properties is largely unknown. Antigenic stimulation, persisting and inefficiently cleared antigen, TCR crossreactivity and defects in clonal homeostasis and apoptosis could all play a role, and will be investigated in this proposal. The hypotheses that Ag stimulation plays a role in the onset of CD8+ TCE will be investigated using Ags that the animal had not been exposed to. Dependence of TCE maintenance and expansion on Ag: MHC stimulation, including that by persisting Ag, will be tested by transferring TCE into MHC- deficient animals and by transferring APCs from old or young primed mice into naive ones. The ability of the clones to undergo apoptosis and respond to IL-15, a cytokine critical for the maintenance of CD8 memory cells, will be investigated in vitro and in vivo. Finally, results suggest that there is a fundamentally new mechanism of homeostatic control of peripheral T cell diversity that breaks down in senescence. The existence and operation of this mechanism will be assessed in young and old mice. The studies should elucidate the mechanisms behind generation and maintenance of TCE and further clarify the impact of TCE on the senescent immune system.
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