Temporal and Metabolic Regulation of Restimulation-Induced Cell Death (RICD) in Human T Cells

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PROJECT SUMMARY/ABSTRACT PI: Snow, Andrew L. The healthy immune system depends upon a balance of proliferation and death of white blood cells, including B and T lymphocytes, to contain and eliminate infectious pathogens effectively without doing unintended damage to “self” tissues. I have a long-standing interest in elucidating the molecular mechanisms responsible for maintaining immune homeostasis in humans, focusing on B and T cells. One way that activated T cells are instructed to die occurs upon repeated engagement of the T cell receptor (TCR); a process known as restimulation- induced cell death (RICD). This self-regulatory death program protects against excessive expansion of T cells as an immune response unfolds. The long-term objective of my research program is to define specific biochemical signals that convert the TCR signal from proliferation and survival to death, which remain incompletely understood. Our research is informed in part by investigating human immune disorders, caused by single gene defects, that result in dysregulated immune homeostasis. We previously discovered a novel RICD defect in T cells from patients with X-linked lymphoproliferative disease (XLP), which lack expression of SLAM-associated protein (SAP). SAP is required for proper RICD in normal T cells. Using a variety of genetic and biochemical approaches, we illuminated a previously unrecognized network of biochemical signals connecting SAP, NTB-A, and key kinases (e.g. LCK, DGKa), phosphatases (SHP-1), and transcription factors (FOXP3) that regulate TCR signaling and ultimately govern RICD sensitivity in human conventional and regulatory T cells. However, we also learned that several other signaling molecules independent of this network control RICD. Moreover, we discovered that dynamic changes in cellular metabolism also play a major role. Over the next five years, our research will be focused on determining if and how specific co-inhibitory receptors, transcriptional regulators, and metabolic circuits “tune” RICD susceptibility over the entire human T cell response, including early stages of rapid T cell proliferation. Elucidating these critical signaling events will improve our basic understanding of abnormal T cell signaling and cell death in patients with immune disorders beyond XLP. Understanding these molecular interactions should offer new therapeutic targets to control T cell responses by manipulating RICD sensitivity, which could be applied to numerous clinical contexts in which culling excess T cells (e.g. autoimmunity, lymphoproliferative disease) or boosting T cell responses (e.g. infection, vaccination, cancer) could help ameliorate disease.