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+CD28- 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+CD28- 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 DMAdemethylates 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+CD28- 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+CD28- and CD4+CD28+ T cells from RA patients and elderly subjects, and to CD4+CD28+ 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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Fuldner, Rebecca A
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Gorelik, Gabriela; Sawalha, Amr H; Patel, Dipak et al. (2015) T cell PKC? kinase inactivation induces lupus-like autoimmunity in mice. Clin Immunol 158:193-203
Gorelik, Gabriela J; Yarlagadda, Sushma; Patel, Dipak R et al. (2012) Protein kinase C? oxidation contributes to ERK inactivation in lupus T cells. Arthritis Rheum 64:2964-74
Gorelik, Gabriela; Richardson, Bruce (2010) Key role of ERK pathway signaling in lupus. Autoimmunity 43:17-22
Li, YePeng; Liu, Ying; Strickland, Faith M et al. (2010) Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol 45:312-22
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
Basu, Dhiman; Liu, Ying; Wu, Ailing et al. (2009) Stimulatory and inhibitory killer Ig-like receptor molecules are expressed and functional on lupus T cells. J Immunol 183:3481-7
Hewagama, Anura; Richardson, Bruce (2009) The genetics and epigenetics of autoimmune diseases. J Autoimmun 33:3-11
Gorelik, Gabriela; Richardson, Bruce (2009) Aberrant T cell ERK pathway signaling and chromatin structure in lupus. Autoimmun Rev 8:196-8
Loeser, R F; Im, H-J; Richardson, B et al. (2009) Methylation of the OP-1 promoter: potential role in the age-related decline in OP-1 expression in cartilage. Osteoarthritis Cartilage 17:513-7
Liu, Ying; Kuick, Rork; Hanash, Samir et al. (2009) DNA methylation inhibition increases T cell KIR expression through effects on both promoter methylation and transcription factors. Clin Immunol 130:213-24

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