T cell tolerance not only is critical in preventing autoimmune diseases but also contributes to tumor tolerance. T cell anergy and regulatory T cells (Treg) are two major forms of peripheral T cell tolerance. However, the specific mechanisms that control T cell anergy and Treg are still not well understood. Rapamycin has been utilized as an immunosuppressant for decades. Its target, the mammalian target of rapamycin (mTOR), is a serine threonine kinase that plays crucial roles in multiple cellular processes by regulating nutrient uptake, transcription, translation, autophagy, and cell survival. mTOR forms two signaling complexes (mTORC1 and mTORC2) with distinct signaling properties and sensitivities to rapamycin. Recent evidence has established mTOR as a crucial regulator for effector T cell differentiation, T cell anergy, inducible regulatory T cell differentiation, and memory T cell responses to viral pathogens. However, the pathways leading to mTOR activation in T cells and the importance of tight control of mTOR activity remain poorly understood. The objective of this proposal is to improve the understanding of mTOR signaling and the importance of the tumor suppressor tuberous complex 1 (TSC1) as a critical regulator for mTOR in the control of T cell tolerance. Using genetically manipulated mice and cell line models, we have recently revealed that the RasGRP1-Ras- Mek1/2-Erk1/2 pathway is critical for both mTORC1 and mTORC2 activation in T cells following T cell receptor (TCR) stimulation. We and others have also demonstrated that TSC1 inhibits mTORC1 but promotes mTORC2 signaling in T cells and is important for normal T cell homeostasis. Our central hypotheses for this proposal are 1) multiple signaling cascades downstream of the TCR control mTOR activation and 2) TSC1 is a critical regulator for inducible Treg and T cell anergy by tight contro of mTORC1 and mTORC2 signaling. With strong preliminary data, we plan to test our hypotheses by pursuing three specific aims.
In aim 1, we will investigate the mechanisms that control mTOR activation in T cells. We will test the hypothesis that Erk1/2 phosphorylate multiple substrates to promote mTORC1 and mTORC2 activation.
In aim 2, we will determine how TSC1 controls T cell anergy.
In aim 3, we will determine how TSC1 controls inducible Treg and helper T cell differentiation. The proposed studies will provide new insight into the understanding of mTOR signaling, the importance of TSC1 in T cells, and the mechanisms modulating T cell tolerance.

Public Health Relevance

Proper control of T cell activation and tolerance is important in preventing the pathogenesis of autoimmune diseases and mounting effective immune responses against cancer and pathogens. Studies in this proposal are expected to improve the understanding of mechanisms that regulate T cell activation and tolerance, which will have potential implications for the development of novel therapeutic strategies for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI101206-01
Application #
8346442
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Lapham, Cheryl K
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$392,500
Indirect Cost
$142,500
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Shin, Jinwook; Wang, Shang; Deng, Wenhai et al. (2014) Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function. Proc Natl Acad Sci U S A 111:E776-83
Krishna, Sruti; Yang, Jialong; Wang, Hongxia et al. (2014) Role of tumor suppressor TSC1 in regulating antigen-specific primary and memory CD8 T cell responses to bacterial infection. Infect Immun 82:3045-57
Wu, Jinhong; Yang, Jialong; Yang, Kai et al. (2014) iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest 124:1685-98
Mousallem, Talal; Yang, Jialong; Urban, Thomas J et al. (2014) A nonsense mutation in IKBKB causes combined immunodeficiency. Blood 124:2046-50
Wu, Jinhong; Shin, Jinwook; Xie, Danli et al. (2014) Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity. J Immunol 192:2643-50
Hamilton, Kristia S; Phong, Binh; Corey, Catherine et al. (2014) T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci Signal 7:ra55
Krishna, Sruti; Zhong, Xiaoping (2013) Role of diacylglycerol kinases in T cell development and function. Crit Rev Immunol 33:97-118
Wu, Jinhong; Shen, Shudan; Yang, Jialong et al. (2013) Diacylglycerol kinase zeta positively controls the development of iNKT-17 cells. PLoS One 8:e75202
Shin, Jinwook; Zhang, Ping; Wang, Shang et al. (2013) Negative control of mast cell degranulation and the anaphylactic response by the phosphatase lipin1. Eur J Immunol 43:240-8
Shin, Jinwook; Xie, Danli; Zhong, Xiao-Ping (2013) MicroRNA-34a enhances T cell activation by targeting diacylglycerol kinase ýý. PLoS One 8:e77983

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