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New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and The Children’s Hospital of Philadelphia, Philadelphia, PA 19104

The vertebrate immune system has evolved to deal with invasive pathogens, but this adaptation comes at the expense of immunopathology. Among a number of mechanisms that coevolved to control adaptive immunity is anergy, the functional inactivation of T lymphocytes that respond to Ag in the absence of inflammation. In this review, I highlight a series of intracellular proteins in quiescent T cells that function to integrate signals from Ag, costimulatory, and growth factor receptors. These factors ensure that cells that fail to engage all three pathways are shunted into an alternative transcriptional program designed to dissuade them from participating in subsequent immune responses. Recent studies indicate that anergy is the combined result of factors that negatively regulate proximal TCR-coupled signal transduction, together with a program of active transcriptional silencing that is reinforced through epigenetic mechanisms.

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¹ Address correspondence and reprint requests to Dr. Andrew D. Wells, University of Pennsylvania, Children’s Hospital of Philadelphia, 916E Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: adwells{at}mail.med.upenn.edu

² Abbreviations used in this paper: Treg, regulatory T cell; ARRE, Ag receptor response element; CD28RE, CD28 response element; CDK, cyclin-dependent kinase; CREM, cAMP response element modulator; DGK, diacylglycerol kinase; GRAIL, gene related to anergy in lymphocytes; HAT, histone acetyltransferase; HDAC, histone deacetylase; IKK, IB kinase; PLC, phospholipase C; mTOR, mammalian target of rapamycin; PKC, protein kinase C; TRAF, TNFR-associated factor.

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