Regulating peripheral T cell tolerance

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DESCRIPTION (provided by applicant): Most T cells in healthy individuals are in a naïve 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 naïve 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 DGKα and ζ, the major isoforms expressed in T cells, causes na�ve T cells to lose quiescence, leading to acquisition of effector function. Furthermore, DGKα and ζ 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 DGKα and ζ deficient mice as a model and to perform thorough structure/function analysis of DGKζ in primary T cells using newly generated mice that conditionally express WT and mutant GFP-DGKζ fusion proteins. We will test the hypotheses that DGKα and ζ modulate multiple signaling pathways including mTOR signaling to ensure T cell tolerance and quiescence and that DGKζ 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 DGKα and ζ to ensure CD8 T cell quiescence. In Aim 2, we will determine structural features critical for DGKζ 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 DGKζ fulfills its critical regulatory roles in T cells.