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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-HAI-K (09))
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Johnson, David R
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Beth Israel Deaconess Medical Center
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Lo, Mindy S; Tsokos, George C (2018) Recent developments in systemic lupus erythematosus pathogenesis and applications for therapy. Curr Opin Rheumatol 30:222-228
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