Characterization of the pathways controlling primary T cell fate following antigen stimulation by using adenoviral-mediated gene delivery

The immune system is a complex network consisting of various cell types to protect organisms from foreign pathogens. There are two types of immunity that have been defined based on the immune specificity. One is called innate immunity that defends hosts from any foreign pathogens non-specifically. The other is called adaptive immunity that prevents organisms from specific pathogen invasion. T lymphocytes play pivotal roles in adaptive immunity. T cells carry out their function following recognition of specific peptide antigens presented by APCs (antigen presenting cells) via interacting with APCs. The T cell:APC interaction is initiated with the contact between TCRs (T cell receptors) on T cells and MHC:peptide complexes on APCs. With the help of costimulatory interaction engagement between T cells and APCs, T cells are optimally activated and proliferate in order to clear the pathogens. Upon repetitive stimulation, activated T cells will undergo apoptosis to maintain homeostasis as well as self-tolerance.; It has been well accepted that the TCR activated CDK/Rb/E2F pathway is critical in controlling T cell cycle progression. In addition, it has been suggested that costimulation activated NFκB signaling pathway is important for T cell survival. However, the interactions between these two pathways are poorly defined. During my graduate studies, I tried to address whether there is any interaction between the cell cycle and NFκB signaling pathways, and how such interactions affect T cell fate decision. In order to address these and other questions, an efficient method to manipulate gene expression in primary T cells was required. In order to facilitate adenoviral mediated gene transfer into T cells. I developed mice transgenic for the Coxsackie-adenoviral receptor (CAR), in which CAR is specifically expressed on the surface of T cells. Genes can be efficiently introduced into CAR Tg T cells via adenoviral mediated gene transfer, which is every inefficient without the CAR transgene.; By inhibiting the NFκB activities in CAR Tg T cells via adenoviral mediated overexpression of mIKB, I demonstrated that NFκB activities are required for T cell survival following antigen stimulation. Surprisingly, I found that NFκB activities are required for the downregulation of p73 mRNA expression, whose upregulation requires the activation of the CDK/Rb/E2F pathway. Furthermore, I demonstrated that apoptosis resulted from the inhibition of NFκB activities is p73 as well as p53 gene dependent. Thereby, we conclude that the pro-survival function of NFκB appears, at least in part, to be due to its ability to antagonize the apoptosis induced by the p73 and p53 genes. During T cell activation, we propose that NFκB serves as a checkpoint to ensure that only T cells receiving optimal activation go through cell cycle and proliferate instead of apoptosis.