Influence of ligand on specification of gamma/delta fate and function

Research Inst Of Fox Chase Can Ctr, Philadelphia PA

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Abstract

The goal of this proposal is to understand the molecular processes controlling ?? lineage commitment and specification of effector fate. Both events occur during development in the thymus; however, our understanding of the developmental cues controlling these fate decisions remains incomplete. Accumulating evidence suggests that both ?? lineage commitment and effector fate are influenced by differences in T cell receptor (TCR) signal strength. The differences in TCR signal strength influence fate by inducing Id3, an antagonist of E protein DNA binding. While E proteins clearly play a central role, their influence on developmental outcomes is almost certainly modulated by additional transcription factors and the extracellular signals that control their expression and function. Accordingly, these fate decisions are too complex to be understood by focusing on one gene or pathway and so require the comprehensive, network-based approach pioneered by Murre. We will employ this approach to elucidate the E protein targets that are crucial for these fate decisions, as well as, the DNA-binding proteins and signaling cascades with which they cooperate. In doing so, we will exploit the ? ?TCR transgenic (Tg) model, KN6, whose known selecting ligand, the non-classical MHC-I molecule T10d, can be manipulated to alter TCR signaling. In Aiml, we will employ KN6 Tg mice, and endogenous T10/22 reactive ?? progenitors, to determine how specific ablation of the T10/22 ligand affects ?? lineage commitment, repertoire selection, and effector function. Aim2 will exploit the network approach described above to determine how IdS is able to promote development of V?2+ and V?3+ ?? T cells, but restrains the development of V?1.1+ innate ?? T cells. Aim3 will exploit our novel marker of ?? lineage commitment, CD73, to determine whether ?? lineage commitment and specification of effector fate are separable or occur simultaneously. The molecular processes defining lineage commitment will be elucidated through the comprehensive network being assembled in Project 4, and by genetic tests of the resulting molecular model. These efforts require the capabilities of all program members and promise to reveal critical new insights into how ?? T cell development is controlled.