Memory T cells are not identical with naive T cells: they have surface markers expressed at different levels, they are more capable in handling intense triggering, and they mount a more effective anamnestic immune response. The experiments we propose aim at understanding the basic mechanisms that lead to the acquisition of memory in T cells, the biology of the activation of typical memory T cells in a secondary immune response and the control of the size of the memory T cell pool. 1. Using a panel of memory T cell clones specific for the same antigen, we will correlate their level of Ca2+ sensitivity with their functional and phenotypic characteristics. This analysis should also lead to the identification of cells that represent intermediate stages in the transition from naive to memory T cells. We will investigate, with the help of H-Y specific TCR transgenic mice, whether the ability to down regulate high levels of intracytoplasmic Ca2+ is a unique property of CD4 memory T cells, or whether CD8 memory T cells also exhibit such a capability. 2. We will determine whether CIF and/or the association between CD28 and PI 3-K are involved in the differential regulation of [Ca2+]I in naive and memory T cells. We will investigate the effect of TCR-induced zeta-cytoskeleton association in naive and memory T cells and determine in these cells in influence of TCR-induced integrin activation. Using real time fluorescence imaging microscopy, we will analyze, at the single cell level, the fluctuations of [Ca2+]I following activation. 3. We will determine whether the recruitment of a T cell into the high Ca2+ resistant memory pool is influenced by the type of T precursor (fetal versus adult) from which the T cell is derived. We will determine whether the Ca2+ resistant phenotype associated with memory cells in induced or precedes encounter with antigen. 4. To further understand the molecular basis of memory acquisition, we will attempt to identify new candidate molecules which are responsible for the different functional properties observed between naive and memory T cells.
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