The breakdown of T cell tolerance is a pinnacle pathogenic event in rheumatoid arthritis (RA) and precedes the onset of clinical disease by decades. Molecular analyses of T cells supported by this project has led to the discovery that RA T cells are prematurely aged and that senescence supports proinflammatory effector functions. Recent work has connected maldifferentiation of RA T cells with abnormalities in their energy supply and metabolism. Metabolic abnormalities are present in nave CD4 T cells, long before they participate in synovial inflammation, opening the intriguing possibility to prevent autoimmunity by metabolic interference. Nave CD4 T cells in RA patients downregulate the glycolytic enzyme Phosphofructokinase 2 (PFKFB3) and upregulate Glucose-6-phosphate dehydrogenase (G6PD); therefore shunting glucose into the pentose phosphate pathway (PPP). This metabolic abnormality leads to an oversupply of reductive elements (NADPH) and consumption of reactive oxygen species (ROS), resulting in defective oxidant signaling. Mostly affected is the redox-sensing protein kinase Ataxia telangiectasia mutated (ATM), which controls cell cycle behavior. With ATM insufficiency, RA T cells hyperproliferate, loose quiescence and make an early commitment to IL-17 and IFN-? production. This project will define molecular mechanisms that connect metabolic and functional abnormalities in RA T cells, with the aim to identify actionable diagnostic and therapeutic targets. We have developed a panel of pharmacologic and genetic manipulations to mimic PPP overutilization in human T cells, enabling a mechanistic exploration of T cell metabolism and function.
Specific Aim 1 will seek to understand how glucose shunting into the PPP, accumulation of NADPH and loss of ROS affects T cell differentiation, survival and senescence; with a special emphasis on the induction of disease- relevant T follicular helper cells and Treg cells.
Specific Aim 2 will determine how metabolic reprogramming affects the interaction of T cells with B cells, osteoclast precursors and synoviocytes to clarify its impact on autoantibody production, bone erosion and synovial hyperplasia.
In Specific Aim 3, we will examine the regulatory role of inflammatory signals in the glycolytic machinery, specifically in the induction and suppression of PFKFB3 and G6PD.
Specific Aim 4 is designed to discover how oxidant signaling shapes T cell differentiation and lineage commitment. By focusing on ATM, AMPK and mTOR we will define relevant signaling pathways and identify small molecule reagents that can restore ATM and AMPK activation, thus restraining mTOR and mTOR-dependent inflammation.

Public Health Relevance

Rheumatoid arthritis is a chronic inflammatory joint disease caused by a dysfunctional immune system. In patients with RA the 'master regulators' of the immune system, CD4 T cells, are pre-aged and have a defect in their energy supply. This proposal seeks to identify new ways of manipulating the energy metabolism of T cells, such that these T cells can be reeducated and reintegrated into a healthy immune system.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mao, Su-Yau
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kim, C; Fang, F; Weyand, C M et al. (2017) The life cycle of a T cell after vaccination - where does immune ageing strike? Clin Exp Immunol 187:71-81
Goronzy, Jörg J; Weyand, Cornelia M (2017) Successful and Maladaptive T Cell Aging. Immunity 46:364-378
Uribe, Jorge A; Aggarwal, Ishita; Witthayaweerasak, Juthamat et al. (2017) Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis. J Neuroophthalmol :
Watanabe, Ryu; Hosgur, Ebru; Zhang, Hui et al. (2017) Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis. Joint Bone Spine 84:421-426
Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2017) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol :
Yanes, Rolando E; Gustafson, Claire E; Weyand, Cornelia M et al. (2017) Lymphocyte generation and population homeostasis throughout life. Semin Hematol 54:33-38
Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2017) Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A 114:E970-E979
Wen, Zhenke; Shen, Yi; Berry, Gerald et al. (2017) The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway. Sci Transl Med 9:
Watanabe, Ryu; Shirai, Tsuyoshi; Namkoong, Hong et al. (2017) Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. J Clin Invest 127:2725-2738
Shen, Yi; Wen, Zhenke; Li, Yinyin et al. (2017) Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat Immunol 18:1025-1034

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