Defects in the stringently regulated processes that generate and maintain the diverse and self-tolerant pool of T-cells responsible for immunity cause very debilitating human autoimmune and immunodeficiency diseases. Despite decades of evolving therapies, autoimmune diseases still rank among the leading causes of death especially in women and children in the US alone where more than 23 million people are afflicted, at a cost that exceeds $100 billion annually to the economy. As dysfunctional T-cell development and homeostasis frequently underlie autoimmune disease states, development of more effective therapies against these diseases will benefit from resolving major knowledge gaps of the cellular factors and pathways that enable T- cell homeostasis. For example, proteasome-dependent mechanisms control the activity of proteins that mediate survival, metabolism and signal transduction in T-cells but how key homeostatic signals from the T-cell receptor (TCR) and interleukin (IL)-7 are coupled to the ubiquitination machinery is still poorly understood. We recently discovered that the Charged Multivesicular Body Protein-5 (CHMP5) functions as an ?adaptor? during T-cell development to recruit deubiquitinating enzymes that promote client protein stability. New evidence from our laboratory shows that CHMP5 expression is stringently controlled by TCR and IL-7 signals, and that deletion of CHMP5 in peripheral T-cells impaired their homeostasis and was associated with a fully penetrant multi-organ autoimmune condition. Thus, leveraging animal models that allow precise tracking of CHMP5 mutant T-cells, in this proposal we will test the hypothesis that CHMP5 nucleates a critical posttranslational node by which homeostatic signals are integrated to the stability of protein mediators of T-cell survival and tolerance, situating it as a tunable and potential target for modulating T-cells in disease.
In Aim I, we will determine how CHMP5 controls energy metabolism and prosurvival proteins integral to peripheral T-cell survival and function.
In Aim 2, we will elucidate the mechanism of differential CHMP5 stabilization by TCR and IL-7 signals, especially their ability to induce serine phosphorylations that stabilize CHMP5 protein. Additionally, as deletion of the deubiquitinase USP8 depletes CHMP5 proteins in T-cells, we will define the basis of the USP8-CHMP5 interaction. Disrupting this interaction can potentially be utilized to therapeutically deplete T-cell CHMP5. To date, how TCR signal thresholds are translated into thymocyte positive and negative selection remains unclear. Thus, building on evidence that CHMP5 is stabilized by low affinity TCR ligands but degraded by high affinity signals, in Aim 3, we will test the novel paradigm that differential CHMP5 protein stabilization is a thymocyte mechanism to establish central tolerance. These studies will yield insights into long-standing questions on T-cell homeostasis and have the potential to uncover new posttranslational vulnerabilities that can be exploited to therapeutically modulate T-cells in disease especially as dysregulation of the human 9p13.3 chromosomal region location of CHMP5 gene is linked with diseases in multiple tissues.

Public Health Relevance

Autoimmune and immunodeficiency diseases rank among the top ten leading causes of death worldwide and cost over 100 billion dollars to the US economy annually. As these diseases often result from defects in T-cell development and maintenance, herein we propose to elucidate how CHMP5, a factor that we recently identified to finely control protein expression in T-cells, performs a novel critical role in eliminating potentially autoreactive T-cells and in sustaining T-cells in health and disease. Through these studies we expect to gain new insights into the regulation of T-cell survival and identify cellular targets that can be exploited to treat debilitating T-cell-mediated diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Prabhudas, Mercy R
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Case Western Reserve University
Schools of Medicine
United States
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