Most T cells in healthy individuals are in a nave resting or quiescent state. Quiescence ensures the maintenance of the vast repertoire of T cells in a defined space by preventing uncontrolled polyclonal expansion. Recent evidence indicates that T cell quiescence is actively programmed and maintained. However, the mechanisms that control T cell quiescence are poorly understood. The maintenance of steady-state nave CD8 T cells relies on orchestrated signaling from the IL-7 receptor and the T cell antigen receptor (TCR). TCR signaling is initiated after the engagement of the TCR with major histocompatibility complex I molecules loaded with self-peptides. How such tonic TCR signaling is tightly controlled to prevent full T cell activation is poorly understood. Diacylglycerol kinases (DGKs) are enzymes that convert diacylglycerol (DAG) to phosphatidic acid (PA), both important second messengers involved in activating in multiple signaling pathways and regulate diverse cellular processes and functions. In mammals, ten DGK isoforms exist yet their physiological functions are poorly understood. We have found that deficiency of both DGK? and ?, the major isoforms expressed in T cells, causes na?ve T cells to lose quiescence, leading to acquisition of effector function. Furthermore, DGK? and ? double deficient mice develop severe autoimmune diseases with T cells play critical roles. The objectives of this application are to investigate mechanisms that control CD8 T cell quiescence using conditional DGK? and ? deficient mice as a model and to perform thorough structure/function analysis of DGK? in primary T cells using newly generated mice that conditionally express WT and mutant GFP-DGK? fusion proteins. We will test the hypotheses that DGK? and ? modulate multiple signaling pathways including mTOR signaling to ensure T cell tolerance and quiescence and that DGK? directs its localizations and interactions via distinct structural domains/motifs, enabling it to function in multiple subcellular compartments as a critical regulator in T cells. We will pursue the following two specific aims.
In Aim 1, we will investigate mechanisms that are controlled by DGK? and ? to ensure CD8 T cell quiescence.
In Aim 2, we will determine structural features critical for DGK? to function as a critical regulator for T cell development and tolerance. Studies proposed in this application will provide novel insight into the signaling control of T cell development and quiescence and how DGK? fulfills its critical regulatory roles in T cells.
Autoimmune diseases are serious health problems that inflict millions of people. Proper control of T cell quiescence is important for T cell homeostasis, tolerance, and effective immune responses. Studies in this proposal are expected to improve the understanding of mechanisms that control T cell development, tolerance, and quiescence, which should lead to the development of novel therapeutic strategies for patients with autoimmune diseases.
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