The outcome of TCR recognition is dictated by the context in which the antigen is recognized. While TCR engagement (Signal 1) heralds recognition, whether this recognition will lead to an immunogenic response is dictated by the presence of costimulatory molecules (Signal 2) on the APC. Furthermore, cytokines such as IL-12, IFN-?, IL-4, IL-6 and TGF-? in the inflammatory milieu play critical roles in skewing T cell differentiation. Based on these environmental cues T cells may differentiate into effector subsets characterized by TH1, TH2 and TH17 cells or regulatory cells characterized by Foxp3 expression, LAG-3 expression and IL-10 secretion. We propose that the highly evolutionarily conserved threonine/serine protein kinase the mammalian Target of Rapamycin (mTOR) plays a critical role in integrating these cues and dictating the outcome of antigen recognition. In an effort to understand the mechanisms and pathways by which mTOR regulates T cell function we generated conditional mTOR knockout mice in T cells. mTOR deficient T cells develop normally and produce normal levels of IL-2 upon initial stimulation. However, TCR engagement in the absence of mTOR renders such cells anergic, as revealed by a failure to produce IL-2 and IFN-?. Furthermore, mTOR deficient T cells fail to differentiate into TH1,TH2 or TH17 effector cells. Instead, under normally activating conditions, both in vitro and in vivo these cells develop into regulatory T cells. In this proposal we will employ mTOR null, Rheb null, Rictor null and TSC2 null T cells to determine the role of TORC1 and TORC2 in regulating T cell activation and adaptive effector versus regulatory lineage commitment. Using in vivo models of tumor immunity, viral infection, allergen, EAE and bone marrow transplantation we will further determine the role of mTOR and its downstream signaling in regulating immune responses. Our approach will have important implications with regard to the rationale design of immunosuppressive agents for the treatment of autoimmune disorders and organ transplantation as well as devising strategies to enhance anti-tumor immunity.

Public Health Relevance

In this proposal we will test the hypothesis that mTOR plays a unique and central role in regulating adaptive effector and regulatory T cell lineage commitment. These studies should provide important insight into the regulation of T cell mediated immunity. In addition, our findings will have potential implications for the development of novel therapeutic regimens for the treatment of autoimmunity and the prevention of graft rejection in transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077610-04
Application #
8277329
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$401,841
Indirect Cost
$156,816
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Heikamp, Emily B; Patel, Chirag H; Collins, Sam et al. (2014) The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol 15:457-64
Lo, Ying-Chun; Lee, Chen-Fang; Powell, Jonathan D (2014) Insight into the role of mTOR and metabolism in T cells reveals new potential approaches to preventing graft rejection. Curr Opin Organ Transplant 19:363-71
Thornton, K A; Chen, A R; Trucco, M M et al. (2013) A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma. Int J Cancer 133:997-1005
Powell, Jonathan D; Heikamp, Emily B; Pollizzi, Kristen N et al. (2013) A Modified Model of T-Cell Differentiation Based on mTOR Activity and Metabolism. Cold Spring Harb Symp Quant Biol :
Delgoffe, Greg M; Powell, Jonathan D (2012) Exploring functional in vivo consequences of the selective genetic ablation of mTOR signaling in T helper lymphocytes. Methods Mol Biol 821:317-27
Hagan, Robert S; Powell, Jonathan D (2012) Targeted immunosuppression: no longer naive. Clin Immunol 142:95-6
Powell, Jonathan D; Pollizzi, Kristen N; Heikamp, Emily B et al. (2012) Regulation of immune responses by mTOR. Annu Rev Immunol 30:39-68
Powell, Jonathan D; Pollizzi, Kristen (2012) Fueling memories. Immunity 36:3-5
Delgoffe, Greg M; Pollizzi, Kristen N; Waickman, Adam T et al. (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12:295-303
Powell, Jonathan D; Delgoffe, Greg M (2010) The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33:301-11

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