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 #
5R01AI077610-05
Application #
8471047
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
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$377,731
Indirect Cost
$147,407
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Oh, Min-Hee; Collins, Samuel L; Sun, Im-Hong et al. (2017) mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages. Cell Rep 20:2439-2454
Patel, Chirag H; Powell, Jonathan D (2017) Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr Opin Immunol 46:82-88
Bettencourt, Ian A; Powell, Jonathan D (2017) Targeting Metabolism as a Novel Therapeutic Approach to Autoimmunity, Inflammation, and Transplantation. J Immunol 198:999-1005
Chornoguz, Olesya; Hagan, Robert S; Haile, Azeb et al. (2017) mTORC1 Promotes T-bet Phosphorylation To Regulate Th1 Differentiation. J Immunol 198:3939-3948
Sadtler, Kaitlyn; Estrellas, Kenneth; Allen, Brian W et al. (2016) Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells. Science 352:366-70
Pollizzi, Kristen N; Sun, Im-Hong; Patel, Chirag H et al. (2016) Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat Immunol 17:704-11
Prevot, Nicolas; Pyaram, Kalyani; Bischoff, Evan et al. (2015) Mammalian target of rapamycin complex 2 regulates invariant NKT cell development and function independent of promyelocytic leukemia zinc-finger. J Immunol 194:223-30
Leone, Robert D; Lo, Ying-Chun; Powell, Jonathan D (2015) A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J 13:265-72
Delgoffe, Greg M; Powell, Jonathan D (2015) Sugar, fat, and protein: new insights into what T cells crave. Curr Opin Immunol 33:49-54
Sharma, Madhav D; Shinde, Rahul; McGaha, Tracy L et al. (2015) The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv 1:e1500845

Showing the most recent 10 out of 43 publications