Peripheral T cells from T cell receptor Vb5 transgenic B6 mice undergo a chronic selection against transgene expression among cells in both CD4 and CD8 compartments. This selection occurs in the lymphoid periphery, and is driven by a superantigen encoded by the mammary tumor virus MTV-8. The result of this age-dependent selective process, which occurs with faster kinetics in CD4 T cells, is an inversion of the CD4:CD8 ratio, an increase in T cells that express endogenous TCR b chain genes, and a gradual loss of total T cells in Vb5 transgenic mice. Thus, this system offers an experimental example of the age-dependent cumulative effects of weak selective forces in molding the TCR repertoire, even in older animals with low thymic output. Furthermore, CD4 and CD8 T cells that have been marked for deletion become activated before they are rendered anergic to signals through their TCRs. Unlike their CD4 counterparts, CD8 T cells that are slated for deletion downregulate TCRs and coreceptors. The CD8low compartment in Vb5 transgenic mice is unstable, being characterized by the rapid entry and exit of cells. The proposed experiments are designed to 1) investigate the kinetics, reversibility, and in vivo function of CD8low cells in the presence and absence of antigen, 2) determine whether B cells, CD4 molecules or cells of the CD4 lineage are required to target CD Vb5 T cells for deletion, 3) analyze the diversity of the expressed TCR b chain repertoire and the status of the transgene in Vb5- TCRab+ T cells in Vb5 transgenic mice, and 4) define the strength of the interaction that signals CD8 T cells to enter a deletional pathway. These experiments will shed light on how the cell interprets the overall nature of the TCR-mediated interaction to determine where to enter the continuum between tolerance induction, partial activation, and full activation, whether deletional intermediates can be rescued from the executioner to serve an in vivo function, and whether aging in part reflects the gradual accumulation of cells slated for deletion.
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