Grant: Discovery Grants Program - Individual

We will investigate the role of a protein called terminal deoxynucleotidyl transferase (TdT) in generation of antiviral CD8+ T cell responses. CD8+ T cells comprise an important line of defense against disease-causing viruses. They recognize viral antigens (i.e., molecules considered by the immune system as foreign) and convert to cytotoxic T lymphocytes (CTLs) capable of eliminating virus-infected cells. It is well known that mammalian T cell repertoire consists of a huge number of CTL precursors, each bearing a "pre-made" antigen receptor of unique specificity. The diversity of T cell repertoire results from the function of several key molecules including TdT during T cell development in the thymus. Although viral propagation inside host cells generates thousands of virus-derived peptides and despite the fact that adult T cell pools contain CTL precursors specific for many (if not all) of these peptides, only a limited number of CTL clones rise to the task of detecting viral antigens and combating viral invaders. The magnitude of responses among these few clones varies to a great extent, leading to the establishment of a conserved hierarchy among them. This phenomenon is called immunodominance. Many consider immunodominance an obstacle to successful immune responses targeting as many antigenic sites as possible. It is therefore important to understand how immunodominance hierarchies are shaped. While several factors vis-à-vis peptide generation within host cells have been shown to contribute to immunodominance, only little is known about the relationship between early T cell development in the thymus and dominance hierarchies of CTLs induced in response to viruses encountered later in life. Our preliminary data point to a role for TdT as a missing link between the two phases. We will use modern cellular and molecular techniques and multiple model systems to reveal the importance of TdT in dictating dominance hierarchies of virus-specific T cells. The findings of this study are expected to advance our understanding of CD8+ T cell biology and immunodominance and to introduce a novel biological function for TdT beyond its well-established role during T cell development.