INTRINSIC VS ENVIRONMENTAL IMPACT ON T CELLS OF AGED

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION: The overall goal of this project is to define aging-related alterations of T cells, both intrinsic to T cells and to the aged environment. Past studies in collaboration with Dr. Susan Swain have shown that TCR transgenic CD4 T cells, in the absence of cognate antigen, do not convert to the memory phenotype during aging and show deficiencies in IL-2 production and proliferation in vitro which is reversed by provision of exogenous IL-2. Preliminary findings indicate that naive TCR transgenic CD8 T cells do not show intrinsic aging-related defects. Additionally, preliminary findings indicate that activation of transferred TCR transgenic CD8 T cells in vivo by immunization results in a delayed response. Furthermore, data are presented that show that this delay could be partially reversed by co-transfer of splenic dendritic cells from young mice. Aim 1 will complete the analysis of intrinsic defects in aged CD4 and CD8 T cells in non-immunized TCR transgenic mice. One additional CD4TCR transgenic strain (besides the AND strain previously studied), and 2 additional CD8 strains will be used. Particular focus will be made on analyzing parameters of CD8 TCR transgenic T cell response. In Aim 2, the impact of the aged environment on CD8 responses will be studied. Adoptive transfers of CD8 TCR transgenic cells into old and young hosts will be performed, followed by immunization and measurement of CD8 responses. Aim 3 will follow-up on the finding that young splenic dendritic cells can reverse CD8 T cell defects in vivo. Phenotypic and functional analyses of aged and young dendritic cells, both in vitro and in vivo, will be performed. Aim 4 will evaluate the ability of aged dendritic cells to function in a model of cross-presentation which has been shown to lead to peripheral tolerance. Insulin-HA transgenic mice will be used.