| The immune system requires both a great diversity of functional proteins and the ability of individual cells to adapt and respond to rapidly changing conditions in a quick and precise manner. The nature and magnitude of immune responses determines the outcome and duration of infection. Antigenic immunological memory, maintained by memory T and B lymphocytes, is at the core of successful adaptive immunity. However, uncontrolled immune responses can be damaging to our system. The deregulation of gene expression may result in loss of proper function and lead to pathogenesis. To overcome these problems, the immune system uses several post-transcriptional mechanisms of gene regulation, such as alternative splicing and microRNA-mediated regulation. However, on a genome-wide scale, little is known about the key post-transcriptional regulators that orchestrate molecular networks which govern adaptive immune responses. Therefore, understanding what roles these mechanisms play in shaping signaling network circuitry in lymphocyte activation will advance our understanding of post-transcriptional immune regulation.;Additionally, novel impacts of alternative splicing during T and B cell activation were revealed and provided evidence for a large number of molecular networks populated as a function of time and activation by alternatively spliced genes. These findings demonstrated that transcriptional diversity was greatly increased by alternative splicing.;Finally, microRNA-regulated gene circuitry in activated lymphocytes was determined and revealed that during antigen-driven activation, differential upregulation of specific microRNAs regulates T lymphocyte activation by targeting highly differentially expressed genes involved in networks critical for cell activation, proliferation, and survival. These findings elucidated negative-feedback loops under miRNA-mediated post-transcriptional regulation that serve to restrain T cells activation.;This thesis demonstrated profound changes in blood cell composition and immune activation early post-transplantation and revealed that each cell subset expresses distinct functional pathways and programs. These changes illuminated a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant. |
