application): Aged mice and humans display limited T cell diversity, owing, in part, to the presence of clonal T cell populations. Why and how are these cells generated, and what endows them with selective survival, growth and/or expansion properties are not known. Antigenic stimulation may be necessary for their onset and/or survival and expansion. Defects in clonal homeostasis, particularly in the mechanisms that ensure clonal constriction by apoptosis, could also contribute. Furthermore, clonal T cells may influence the immune system of the elderly. They could affect the outcome of the immune response by limiting the available T cell repertoire, and/or by disturbing cytokine balances necessary for a productive and flexible immune response. This proposal sets out to elucidate the above questions. The hypothesis that antigen stimulation plays a role in the onset of clonal expansion of CD8 + T cells will be investigated in murine model, using antigens that the animal had not been exposed to. Dependence of the clones on antigen: MHC stimulation for survival/expansion will further be tested in transfer experiments, using lymphocyte-deficient Rag; and MHC class I' and II' animals. The ability of the clones to undergo apoptosis will be investigated in vitro and in vivo. The hypothesis that clonal T cells may influence the senescent immune system by cytokine secretion will be addressed by investigating cytokine secretion of clonal T cells. Due to a recommended three year duration of the present proposal, other experiments related to this hypothesis will be proposed elsewhere. The hypothesis that T cell clones hamper the immune response by constricting the available T cell repertoire is strongly supported by our preliminary data. It will be further investigated in two CD8+ and one CD4+ systems where TCR utilization is moderately, heavily, or completely restricted, and in one TCR transgenic model, where the restriction is also very heavy. Strength, diversity and in vivo protective capacity of T cell responses will be evaluated. These studies should elucidate the biological impact of clonal T cells on the senescent immune system.
Showing the most recent 10 out of 16 publications
