A senescent T cell subset, characterized by the absence of CD28, develops with aging, in chronic inflammatory diseases like rheumatoid arthritis (RA), and in acute coronary syndromes. The CD4+ subset is proinflammatory and cytotoxic, and is found in inflamed synovium as well as atherosclerotic plaques of patients dying from myocardial infarction, suggesting they participate in autoimmune disease processes. The CD4+ subset aberrantly expresses killer-cell immunoglobulin-like receptor (KIR) genes and perforin, normally found on NK cells, and overexpresses IFN-y, LFA-1, and CD70. The reason for the aberrant gene expression is unknown. In preliminary studies we found that normal T cells have the transcription factors necessary for KIR, perforin, IFN-y, LFA-1 and CD70 expression, but expression of these genes is suppressed by methylation of crucial regulatory elements, and demethylation of these elements is sufficient to promote transcription. Further, we found that total T cell DMA demethylates with age and in RA, due in part to decreases in DNA methyltransferases (Mtase), and that inhibiting T cell ERK and JNK signaling to mimic the decreased signaling that occurs with aging decreases DNA Mtase expression and demethylates DNA. Finally, we found that CD28 provides costimulatory signals increasing DNA Mtase expression. We hypothesize that DNA hypomethylation, caused by decreased JNK and/or ERK signaling, results in the overexpression of KIR, perforin, IFN-y, LFA-1 and CD70 in the CD4+ subset in aging and RA, conferring pro-inflammatory and cytotoxic functions. This will be tested in 3 specific aims. We will: 1) Compare methylation status of regulatory elements and expression of the candidate genes in CD4+ and CD4? T cells from RA patients and elderly subjects, and to CD4? cells in controls, 2) Compare DNA Mtase levels in the same T cell subsets, then selectively decrease DNA Mtase levels in normal T cells and examine the effects on candidate gene methylation and expression, and 3) Compare ERK and JNK pathway signaling in the same T cell subsets, and examine the effects of decreased signaling on DNA Mtase expression and candidate gene methylation, expression and function. These studies will identify mechanisms modifying gene expression in this pathologic subset, and suggest ways to restore normal gene expression in these cells. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG025877-01A1
Application #
7049309
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fuldner, Rebecca A
Project Start
2006-03-15
Project End
2011-02-28
Budget Start
2006-03-15
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$312,284
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Chen, Yingxuan; Gorelik, Gabriela J; Strickland, Faith M et al. (2010) Decreased ERK and JNK signaling contribute to gene overexpression in ""senescent"" CD4+CD28- T cells through epigenetic mechanisms. J Leukoc Biol 87:137-45
Liu, Ying; Chen, Yingxuan; Richardson, Bruce (2009) Decreased DNA methyltransferase levels contribute to abnormal gene expression in ""senescent"" CD4(+)CD28(-) T cells. Clin Immunol 132:257-65
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Gorelik, Gabriela; Richardson, Bruce (2009) Aberrant T cell ERK pathway signaling and chromatin structure in lupus. Autoimmun Rev 8:196-8

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