Systemic lupus erythematosus (SLE) is an autoimmune disorder of largely unknown etiology characterized by profound T cell effector dysfunction. SLE T cells produced reduced amounts of interleukin 2 (IL-2) which contributes to the increased rate of infections, decreased generation of cytotoxic and regulatory T cells and decreased ability to eliminate autoreactive T cells through activation-induced cell death. IL-2 production is controlled at the transcription level by factors whose activity is influenced by membrane-initiated signaling events. We established that SLE T cells have increased protein and mRNA levels of the transcriptional repressor, cAMP responsive element modulator (CREM), which we found to bind to the -180 site of the IL-2 promoter and suppress IL-2 gene transcription. CREM also binds to the -57 site of the c-fos promoter which results in decreased expression of c-fos protein and activating protein-1 activity. Normal, unstimulated T cells do not express CREM, but after stimulation they display phosphorylated (p) cAMP responsive element binding protein (CREB) that binds also to the -180 site. We also demonstrated that anti-CD3/TCR autoantibodies activate calcium/calmodulin kinase IV (CaMKIV) which is found primarily in the nucleus where it phosphorylates CREM and histones. CREM recruits histone deacetylase 1 (HDAC1) to the promoters of the IL-2 and c-fos genes which contributes to the repression of their activity. Increased expression of CREM? in SLE T cells represents both increased promoter (newly characterized) activity and alternative splicing. It is hypothesized that cell membrane-initiated signaling processes lead to increased expression and activation of transcription repressors and modification of cellular proteins. We propose, accordingly, to a) establish that CaMKIV translocates to the nucleus of SLE T cells, determine how it becomes activated and whether its presence is crucial in the development of SLE in lupus prone mice;b) identify the functional repercussions of CREM? - mediated recruitment of HDAC1 to the regulation - of aberrant gene expression in SLE T cells, the identification of novel CREM target genes and whether its absence modifies the expression of SLE in lupus-prone mice;and c) determine mechanisms that result in increased production of CREM1 in SLE T cells, that is, increased promoter activity and enhanced alternative exon splicing process. The proposed studies will provide further insights into the molecular origin of defective IL-2 production in SLE patients and identify molecular targets that may be corrected with drugs or biologics. Successful completion will introduce additional mechanisms that lead to the generation of autoantigens that drive autoimmunity.

Public Health Relevance

- PROJECT NARRATIVE: Systemic lupus erythematosus (SLE) afflicts more than one million Americans most of whom are women in the child bearing age. Immune cells from patients with SLE produce decreased production of interleukin-2 and that leads to increased rate on infections and accounts for additional immunoregulatory defects. The proposed studies will explore the mechanisms that lead to decreased production of interleukin-2 in order to identify molecules that we can target for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049954-08
Application #
7541792
Study Section
Special Emphasis Panel (ZRG1-IMM-K (02))
Program Officer
Johnson, David R
Project Start
2001-04-01
Project End
2012-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
8
Fiscal Year
2009
Total Cost
$425,000
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
Wei, Shuo; Yoshida, Nobuya; Finn, Greg et al. (2016) Pin1-Targeted Therapy for Systemic Lupus Erythematosus. Arthritis Rheumatol 68:2503-13
Comte, D; Karampetsou, M P; Tsokos, G C (2015) T cells as a therapeutic target in SLE. Lupus 24:351-63
Lieberman, Linda A; Tsokos, George C (2014) Lupus-prone mice fail to raise antigen-specific T cell responses to intracellular infection. PLoS One 9:e111382
Hedrich, Christian M; Crispín, José C; Rauen, Thomas et al. (2014) cAMP responsive element modulator (CREM) ? mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. J Biol Chem 289:2361-70
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
Mizui, Masayuki; Koga, Tomohiro; Lieberman, Linda A et al. (2014) IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells. J Immunol 193:2168-77
Ichinose, Kunihiro; Zhang, Zheng; Koga, Tomohiro et al. (2013) Brief report: increased expression of a short splice variant of CTLA-4 exacerbates lupus in MRL/lpr mice. Arthritis Rheum 65:764-9
Hedrich, Christian M; Rauen, Thomas; Crispin, Jose C et al. (2013) cAMP-responsive element modulator ? (CREM?) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4-CD8- T cells in health and disease. J Biol Chem 288:31880-7
del Rio, Roxana; McAllister, Ryan D; Meeker, Nathan D et al. (2012) Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C. PLoS Genet 8:e1003140

Showing the most recent 10 out of 63 publications