Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen‐specific tolerance

Anderson, Per; Manzo, Barbara A.; Sundstedt, Anette; Minaee, Sophie; Symonds, Alistair L. J.; Khalid, Sabah; Rodríguez-Cabezas, M. Elena; Nicolson, Kirsty; Li, Suling; Wraith, David C.; Wang, Ping

doi:10.1002/eji.200635883

Cited by 63 publications

(77 citation statements)

References 48 publications

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“…Subsequently, it was determined that Egr-2 could also participate in FasL transcription [9,14]. More recently, our group has identified Egr-2 and Egr-3 as negative regulators of T cell function [15][16][17]. Egr-2 and Egr-3 expression is upregulated in models of anergy in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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TCR-induced NF-AT activation leads to the up-regulation of multiple genes involved in T cell anergy. Since NF-AT is also involved in T cell activation, we have endeavored to dissect TCR-induced activating and inhibitory genetic programs. This approach revealed roles for the early growth response (Egr) family of transcription factors and the Egr coactivator/corepressor NGFI-A-binding protein (NAB)2 in regulating T cell function. TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit T cell function. In this report, we demonstrate that Egr-2 and Egr-3 are induced by NF-AT in the absence of AP-1, while Egr-1 and NAB2 both require AP-1-mediated transcription. Our data suggest that Egr-3 is upstream of Egr-2, and that mechanistically Egr-2 and Egr-3 suppress Egr-1 and NAB2 expression. Functionally, T cells from Egr-2 and Egr-3 null mice are hyperresponsive while T cells from Egr-3 transgenic, overexpressing mice are hyporesponsive. Furthermore, an in vivo model of autoimmune pneumonitis reveals that T cells from Egr-3 null mice hasten death while Egr-3-overexpressing T cells cause less disease. Overall, our data suggest that just as the Egr/NAB network of genes control cell fate in other systems, TCR-induced Egr-1, 2, 3 and NAB2 control the fate of antigen recognition in T cells.

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Section: Introductionmentioning

confidence: 99%

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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“…Because Egr-2 has been previously characterised and found to be highly upregulated in immune tolerance, these results generated from MicroPath are biologically significant because as expected, those genes that were highly expressed in our tolerance Vs activated datasets were found to be insignificantly expressed in our p-KOA6 Vs WTA6 and p-KOA0 Vs WTA0 datasets (from which the Egr-2 gene was knocked out of the cell lines). Amongst these genes, Ap1s1, Shd, Surf6, Vil2, Lilrb4, Tbx21 and Pdcd1lg2 ( Table 2) have been confirmed to be upregulated in the process of immune tolerance [20], all of which were found to exhibit low expression values in our knock-out expression datasets. This consistent gene expression pattern can be seen graphically in Figure 3.…”

Section: Comparison Of Gene Expression Profiles Pertaining To Immune mentioning

confidence: 73%

MicroPath-A pathway-based pipeline for the comparison of multiple gene expression profiles to identify common biological signatures

Khan¹,

Gorle²,

Wang³

et al. 2009

JBiSE

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High throughput gene expression analysis is swiftly becoming the focal point for deciphering molecular mechanisms underlying various different biological questions. Testament to this is the fact that vast volumes of expression profiles are being generated rapidly by scientists worldwide and subsequently stored in publicly available data repositories such as ArrayExpress and the Gene Expression Omnibus (GEO). Such wealth of biological data has motivated biologists to compare expression profiles generated from biologically-related microarray experiments in order to unravel biological mechanisms underlying various states of diseases. However, without the availability of appropriate software and tools, they are compelled to use manual or labour-intensive methods of comparisons. A scrutiny of current literature makes it apparent that there is a soaring need for such bioinformatics tools that cater for the multiple analyses of expression profiles.In order to contribute towards this need, we have developed an efficient software pipeline for the analysis of multiple gene expression datasets, called Micropath, which implements three principal functions; 1) it searches for common genes amongst n number of datasets using a number crunching method of comparison as well as applying the principle of permutations and combinations in the form of a search strategy, 2) it extracts gene expression patterns both graphically and statistically, and 3) it streams co-expressed genes to all molecular pathways belonging to KEGG in a live fashion. We subjected MicroPath to several expression datasets generated from our tolerance-related in-house microarray experiments as well as published data and identified a set of 31 candidate genes that were found to be co-expressed across all interesting datasets. Pathway analysis revealed their putative roles in regulating immune tolerance. MicroPath is freely available to download from: www.1066technologies.co.uk/micropath.

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“…Candidates for NFAT partners in anergy induction are the Egr factors Egr-2 and Egr-3, which were found to be induced and to suppress lymphokine synthesis in anergic A.E7 cells [34,35] and other anergic T cells [36]. When A.E7 cells, a CD4 + Th clone specific for a pigeon cytochrome c (PCC) peptide, were (pre-) treated with ionomycin or PCC peptide for anergy induction, LAT (linker for activation of T cells) was detected as the most upstream sensitive signalling molecule [37].…”

Section: Introduction: Peripheral Tolerance and Nfat Transcription Famentioning

confidence: 99%

“…While anergy induction by NFATc2 mutated in its AP-1 contact sites [28] suggests that NFAT factors alone or together with binding partners other than AP-1 suppress IL-2 synthesis, neither such NFAT partner(s) nor details of NFATmediated suppressive effects on IL-2 synthesis in anergy induction have been unravelled so far. Are the promoters of E3 ligase genes indeed direct targets of NFAT factors, and if so, in which context are they bound and controlled by NFAT?Candidates for NFAT partners in anergy induction are the Egr factors Egr-2 and Egr-3, which were found to be induced and to suppress lymphokine synthesis in anergic A.E7 cells [34,35] and other anergic T cells [36]. When A.E7 cells, a CD4 + Th clone specific for a pigeon cytochrome c (PCC) peptide, were (pre-) treated with ionomycin or PCC peptide for anergy induction, LAT (linker for activation of T cells) was detected as the most upstream sensitive signalling molecule [37].…”

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confidence: 99%

NFAT transcription factors in control of peripheral T cell tolerance

et al. 2006

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The Ca ++ -regulated calcineurin/NFAT cascade is one of the crucial signalling pathways that controls adaptive immunity. However, a number of novel experimental data suggest that, in addition to their role in T cell activation, NFATc transcription factors play also a decisive role in the generation of peripheral tolerance against self-antigens. This function of NFATc factors is mediated by controlling activation-induced cell death and clonal anergy of T helper cells and the activity of regulatory T cells. The multi-functional role of NFATc proteins characterize these transcription factors as key regulators of immunological tolerance and, if dysregulated, of development of autoimmune diseases. Introduction: Peripheral tolerance and NFAT transcription factorsThe primary function of the adaptive immune system of vertebrates is to defend an organism against invading microorganisms and parasites. In addition to the complex molecular mechanisms creating a strong defence system against foreign antigens, several mechanisms have been developed to tolerate self-antigens. With the appearance of the adaptive immune system in jawed fish [1], such tolerance mechanisms have evolved in parallel to suppress the generation of autoimmune and allergic diseases. For the generation of T cell tolerance, one can distinguish two main mechanisms: central tolerance and peripheral tolerance. A comprehensive review of central T cell tolerance has recently been published by Bruno Kyewski and Ludger Klein [2]. Therefore, in this brief review we will focus on mechanisms of peripheral T cell tolerance mediated by the induction of anergy, by suppression through CD4 + CD25 + regulatory T cells (Treg) and by activationinduced cell death (AICD), which, to a large extent, are all controlled by NFAT transcription factors.NFAT (nuclear factor of activated T cells) transcription factors were originally described as nuclear proteins that bind to and control the activity of the interleukin 2 (IL-2) promoter and further lymphokine promoters/ enhancers in T lymphocytes. However, NFAT factors are also expressed in other cell types and regulate the activity of numerous genes that control the generation of cardiac septa and valves in embryonic heart, the formation of blood vessels, the outgrowth of neuronal axons and the differentiation of osteoclasts during bone formation [3][4][5]. Among the five members of the NFAT factor family (Fig. 1A), the activity of four NFATc proteins (NFATc1, c2, c3 and c4) is controlled by the Ca ++ /calmodulin-dependent phosphatase calcineurin (CN) that, by dephosphorylating numerous sites within the regulatory region of NFAT, stimulates cytosolicnuclear translocation and subsequent DNA binding of NFAT factors [3][4][5]. CN is a direct target of two immunosuppressants, cyclosporin A (CsA) and FK506, which, when complexed with immunophilins, can bind to CN and inhibit its enzymatic activity. Without active CN, the activity of NFAT factors is suppressed, T cell activation is blocked and rejection of transplanted organs can be preve...

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Persistent antigenic stimulation alters the transcription program in T cells, resulting in antigen‐specific tolerance

Cited by 63 publications

References 48 publications

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

MicroPath-A pathway-based pipeline for the comparison of multiple gene expression profiles to identify common biological signatures

NFAT transcription factors in control of peripheral T cell tolerance

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