Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by profound T cell effector dysfunction. T cells from SLE patients produce decreased amounts of interleukin 2 (IL-2) in response to antigen stimulation. Sufficient amounts of IL-2 are needed to generate effector cytotoxic and T regulatory cells and for the proper elimination of autoreactive T cells through activation-induced cell death. Because the levels of IL-2 are determined at the IL-2 gene transcription level, we have designed studies to understand the involved mechanisms that lead to transcriptional repression of the IL-2 gene and devise approaches to correct it. We have observed that SLE T cells have increased protein and mRNA levels of the transcriptional repressor, cAMP responsive element (CRE) modulator (CREM), which binds to the -180 (-164/-189) site of the IL-2 promoter and suppress the IL-2 gene transcription. At the same site of the promoter binds the enhancer phosphorylated CRE binding protein (pCREB) and we hypothesize that the ratio of pCREB/CREM determines the transcriptional activity of the IL-2 promoter. We recently observed that a serine/threonine protein phosphatase (PP)2A is aberrantly expressed in SLE T cells and that it dephosphorylates pCREB and therefore, tilts the balance of pCREB/CREM bound at the -180 site of the IL-2 promoter towards CREM. The hypothesis will be tested in three sets of experiments. In the first, it will be established that PP2A is expressed at increased levels in patients with SLE, in the second, the mechanisms whereby increased PP2A activity causes decreased IL-2 production will be deciphered, whereas in the third, the mechanisms that are responsible for the increased expression of PP2Ac in SLE T cells will be explored. The generated data will shed light on to the molecular origin of decreased IL-2 production in SLE T cells that is claimed to be responsible for the decreased generation of cytotoxic T cells and increased rate of infections, the decreased numbers of T regulatory cells and the defective antigen activation-induced T cell death. In addition, the produced information will introduce new approaches to correct the abnormal expression of PP2Ac and reverse the decreased IL-2 production and defective T cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068787-05
Application #
8046428
Study Section
Special Emphasis Panel (ZRG1-HAI-K (09))
Program Officer
Johnson, David R
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2011
Total Cost
$401,668
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Lo, Mindy S; Tsokos, George C (2018) Recent developments in systemic lupus erythematosus pathogenesis and applications for therapy. Curr Opin Rheumatol 30:222-228
Sharabi, Amir; Kasper, Isaac R; Tsokos, George C (2018) The serine/threonine protein phosphatase 2A controls autoimmunity. Clin Immunol 186:38-42
Moulton, Vaishali R; Suarez-Fueyo, Abel; Meidan, Esra et al. (2017) Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective. Trends Mol Med 23:615-635
Kasper, Isaac R; Apostolidis, Sokratis A; Sharabi, Amir et al. (2016) Empowering Regulatory T Cells in Autoimmunity. Trends Mol Med 22:784-797
Apostolidis, Sokratis A; Rodríguez-Rodríguez, Noé; Suárez-Fueyo, Abel et al. (2016) Phosphatase PP2A is requisite for the function of regulatory T cells. Nat Immunol 17:556-64
Moulton, Vaishali R; Tsokos, George C (2015) T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest 125:2220-7
Otomo, Kotaro; Koga, Tomohiro; Mizui, Masayuki et al. (2015) Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice. J Immunol 195:5533-7
Nagpal, Kamalpreet; Watanabe, Katsue Sunahori; Tsao, Betty P et al. (2014) Transcription factor Ikaros represses protein phosphatase 2A (PP2A) expression through an intronic binding site. J Biol Chem 289:13751-7
Grammatikos, Alexandros P; Kyttaris, Vasileios C; Kis-Toth, Katalin et al. (2014) A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus. Clin Immunol 150:192-200
Sunahori, Katsue; Nagpal, Kamalpreet; Hedrich, Christian M et al. (2013) The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T- J Biol Chem 288:21936-44

Showing the most recent 10 out of 24 publications