Transcriptional regulation of T cell tolerance - PubMed (original) (raw)

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Transcriptional regulation of T cell tolerance

Sanmay Bandyopadhyay et al. Semin Immunol. 2007 Jun.

Abstract

Self-reactive T cells that escape negative selection in the thymus must be kept under control in the periphery. Mechanisms of peripheral tolerance include deletion or functional inactivation of self-reactive T cells and mechanisms of dominant tolerance mediated by regulatory T cells. In the absence of costimulation, T cell receptor (TCR) engagement results in unopposed calcium signaling that leads to the activation of a cell-intrinsic program of inactivation, which makes T cells hyporesponsive to subsequent stimulations. The activation of this program in anergic T cells is a consequence of the induction of a nuclear factor of activated T cells (NFAT)-dependent program of gene expression. Recent studies have offered new insights into the mechanisms responsible for the implementation and maintenance of T cell anergy and have provided evidence that the proteins encoded by the genes upregulated in anergic T cells are responsible for the implementation of anergy by interfering with TCR signaling or directly inhibiting cytokine gene transcription.

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Figures

Figure 1

Figure 1. NFAT induces a specific program of gene expression in anergic T cells

TCR engagement without concomitant costimulation results in the unbalance activation of calcium signaling in the absence of full activation of other pathways (i.e. Ras/MAPK, PKC, IKK). Sustained increased intracellular calcium activates the calmodulin (CM) dependent phosphatase calcineurin (Cn) which dephosphorylates NFAT, exposing a nuclear localization signal (NLS) and inducing NFAT nuclear translocation. In the absence of AP-1 proteins, NFAT induces an anergy-inducing program of gene expression. NFAT also upregulates the expression of Egr2 and Egr3 (Egr) that contribute in cooperation with NFAT or in an independent manner, to activate the expression of anergy-inducing genes. The proteins encoded by those genes (e.g. Itch, Grail, Cbl-b, DGKα, Ikaros) will cause dampening of TCR signaling and IL-2 silencing in anergic T cells.

Figure 2

Figure 2. Active mechanisms of transcriptional repression contribute to the implementation and maintenance of anergy in T cells

Anergizing stimuli induce the calcium/NFAT-dependent upregulation of the expression of Ikaros (Ik). In anergic T cells Ikaros binds to the IL-2 promoter and recruits histone deacetylases (HDAC). These enzymes would remove acetyl groups (Ac) from core nucleosome histones (H) leading to the establishment of epigenetic changes that result in stable silencing of the IL-2 gene expression. Other transcriptional repressors (i.e. CREM proteins and Smad3 (C/S)) may be activated by calcium or other signals and bind to the IL-2 promoter also inhibiting IL-2 expression.

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