Control of Recent Thymic Emigrant Survival by Positive Selection Signals and Early Growth Response Gene 1

Schnell, Frederick J.; Kersh, Gilbert J.

doi:10.4049/jimmunol.175.4.2270

Cited by 20 publications

(24 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These conclusions confirm and extend those of Wiest and coworkers, who recently published a similar study using mice in which Egr2 had been deleted from the DN stage onwards [26]. Similar to Egr2 f/f CD4cre thymocytes, Egr-1 and 3 doublydeficient thymocytes are susceptible to apoptosis [14], and in Egr-1 À/À mice, recent thymic emigrants are also relatively fragile [35]. Bcl-2, FasL and Id3, a regulator of E-box proteins, which when knocked out causes defects in positive selection [36], have all been suggested as target genes of all Egr family members, and indeed, both Bcl2 (this study, and [26]) and Id3 [26] are downregulated in response to Egr2 loss during positive selection.…”

Section: Discussionsupporting

confidence: 80%

Early growth response 2 regulates the survival of thymocytes during positive selection

2009

View full text Add to dashboard Cite

The early growth response (Egr) transcription factor family regulates multiple steps during T-cell development. We examine here the role played by Egr2 in positive selection. In double-positive cells, Egr2 is upregulated immediately following TCR ligation, and its expression requires both the MAPK and calcineurin signaling pathways. Inducible transgenic and knockout mice were generated to cause gain-or loss-of-function of Egr2 in double-positive cells, and had reciprocal effects; more mature single-positive cells were made when Egr2 was overexpressed, and fewer when Egr2 was absent. These defects were associated with changes in the survival of positively selected cells rather than perturbation of positive selection or immediate post-selection signaling. The survival function of Egr2 at least partly depends upon its ability to activate the cytokine-mediated survival pathway, likely through negative regulation of both the IL-7R and suppressor of cytokine signaling 1 (Socs1), the molecular switch whose downregulation normally results in restored responsiveness to cytokine signaling following selection. While gain of Egr2 caused a decrease in Socs1 mRNA, loss of Egr2 resulted in downregulation of IL-7R, upregulation of Socs1, and inhibition of Stat5 phosphorylation and IL-7-mediated survival post-selection. Therefore, expression of Egr2 following positive selection links the initial TCR signaling event to subsequent survival of signaled cells. , and Egr3 is also required for the post-b-selection proliferative burst to occur [12]. These transcription factors are also induced rapidly following ligation of the abTCR, both during thymocyte selection [15] and in mature T cells responding to antigen-MHC, where Egr1 has a role in upregulation of IL2 transcription [16], and Egr2 and Egr3 are required for induction of anergy [17,18], and regulate expression of FasL [19,20]. Through its control of self-tolerance, Egr2 has also been implicated in the development of late-onset autoimmune disease [21] and is required for the development and maturation of NKT cells [22].Upregulation of Egr proteins during positive selection is dependent upon the Ras/MAPK pathway [13]. Egr proteins are direct transcriptional targets of ternary complex factor Sap-1, which is itself a substrate of Erk and essential for positive selection [23]. In addition, Egr2 and Egr3 are regulated by calcineurin signaling, likely via NFAT [13,20,22]. Both Egr1 and Egr3 have roles in positive selection. Egr1 overexpression enhances positive selection of cells with low affinity TCR [24]. Conversely, Egr1-deficient mice have impaired positive selection [25]; although the initial TCR signal is transduced, cells stall at the DP to SP transition, resulting in a numerical decrease in CD4 and CD8 SP. Animals doubly deficient for both Egr1 and Egr3 have a similar but more marked selection phenotype, and CD8 differentiation is significantly impaired [14]. For both Egr1 and Egr3, the principal reason for the alterations in SP cell number is a change in the cells' susceptibi...

show abstract

Section: Discussionsupporting

confidence: 80%

Early growth response 2 regulates the survival of thymocytes during positive selection

2009

View full text Add to dashboard Cite

show abstract

“…It is a negative regulator of EGR1 target genes (29). EGR1 is important in positive selection, promoting both maturation to the single-positive stage and the survival of recently emigrated thymocytes (5,78).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes

Kasler

Verdin

2007

Molecular and Cellular Biology

View full text Add to dashboard Cite

Histone deacetylase 7 (HDAC7) is highly expressed in CD4 ؉ /CD8؉ thymocytes and functions as a signaldependent repressor of gene transcription during T-cell development. In this study, we expressed HDAC7 mutant proteins in a T-cell line and use DNA microarrays to identify transcriptional targets of HDAC7 in T cells. The changes in gene expression levels were compared to differential gene expression profiles associated with positive and negative thymic selection. This analysis reveals that HDAC7 regulates an extensive set of genes that are differentially expressed during both positive and negative thymic selection. Many of these genes play important functional roles in thymic selection, primarily via modulating the coupling between antigen receptor engagement and downstream signaling events. Consistent with the model that HDAC7 may play an important role in both positive and negative thymic selection, the expression of distinct HDAC7 mutants or the abrogation of HDAC7 expression can either enhance or inhibit the signal-dependent differentiation of a CD4 ؉ /CD8؉ cell line.The thymic development of T cells is a highly regulated process involving multiple extracellular signals. A complex integration of these signals results in changes in gene expression that can lead to the adoption of different developmental fates. Thymocytes pass two main developmental checkpoints that involve antigen receptor signaling. The first, called ␤-selection, occurs after the first of the two chains of the T-cell receptor (TCR) has been productively rearranged and is required for further developmental progression of thymocytes (24,55,75). After ␤-selection, thymocytes proliferate extensively, rearrange their antigen receptor ␣-chains, and become CD4 ϩ , CD8 ϩ , or double-positive (DP) thymocytes. The subsequent developmental fate of DP thymocytes is determined by signaling interactions with antigen-presenting cells (APCs) in the thymic cortex and medulla, most critically between the TCRs of thymocytes and self peptides bound to the major histocompatibility complex (MHC) molecules of the APCs. Broadly, DP thymocytes can adopt three different developmental fates based on the character of this interaction. The large majority of the thymocytes have no functional interaction between their TCRs and the MHC-self peptide complexes on the APCs, and die of neglect within a few days. Thymocytes expressing TCRs that have an interaction of intermediate strength undergo positive selection, after which they downregulate either the CD4 or CD8 coreceptor and exit the thymus as mature CD4 ϩ or CD8 ϩ T cells. Potentially autoreactive thymocytes, with TCRs that interact strongly with MHC-self peptide complexes, are deleted by an apoptotic process termed negative selection. How this continuum of different antigen receptor signal strengths leads to a discrete set of developmental outcomes, in terms of both lineage determination and survival, is still poorly understood.Numerous extracellular signals not involving the TCR have been implicated in the positive and...

show abstract

“…In contrast, Egr-1 overexpression in the thymus allowed positive selection of thymocytes (31). Egr-1 has also been shown to control survival of mature thymocytes and newly emigrated thymocytes (34). The survival role of Egr-1 in thymocyte development can be explained by its function during activation of the T cell survival cytokine IL-2 and its receptor (35)(36)(37).…”

mentioning

confidence: 99%

Early Growth Response Protein-1 (Egr-1) Is Preferentially Expressed in T Helper Type 2 (Th2) Cells and Is Involved in Acute Transcription of the Th2 Cytokine Interleukin-4

Lohoff

Giaisi

Köhler

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The early growth response gene product Egr-1 has been shown to have great impact on growth, proliferation, and differentiation in a wide variety of cells, including T cells. In this study, we show that Egr-1 is rapidly induced upon T cell stimulation and is expressed predominantly in T helper type 2 (Th2) compared with type 1 (Th1) cells. We further investigate the role of Egr-1 in regulation of the Th2 cytokine interleukin-4 (IL-4) expression. IL-4 is a key Th2 cytokine that regulates humoral immunity and also causes allergic inflammation. Regulation of IL-4 gene transcription in Th2 cells has been shown to be controlled by multiple T cell receptor (TCR)-induced transcription factors. However, only a few transcription factors were shown to be selectively induced in differentiated Th2 cells in response to TCR stimulation. Chromatin immunoprecipitation analysis demonstrates that Egr-1 binds to the IL-4 promoter in vivo upon T cell stimulation. Ectopic expression of Egr-1 enhances endogenous IL-4 mRNA expression and elevates IL-4 promoter activity. We also show that Egr-1, nuclear factor of activated T cell, and NF-B cooperatively bind to an NFAT/NF-B-overlapping IL-4 enhancer element and activate the IL-4 promoter synergistically. Furthermore, we show that antisense oligonucleotides that knock down Egr-1 expression attenuate IL-4 transcription. Our study provides the first evidence that Egr-1 protein is differentially expressed in Th1 and Th2 cells and is involved in the acute phase of the IL-4 transcription in response to TCR stimulation. Interleukin (IL)2 -4 plays a pivotal role in the differentiation of T helper type 2 (Th2) cells that secrete IL-4, IL-5, and IL-13 and in the development of humoral immunity (1-3). IL-4 also plays a central role in the pathogenesis of allergic inflammatory diseases (4, 5). Expression of the IL-4 gene by T cells has been documented to occur at two distinct steps: an initial step of differentiation of naïve CD4 T cells into effector Th2 cells and the acute induction of the IL-4 gene expression in differentiated Th2 cells (6 -9).To date, seven transcription factors, STAT6, GATA-3, RBPJ, c-Maf, NFAT, IRF4, and the AP-1 family protein JunB, have been implicated in Th2-specific regulation of IL-4 transcription (6, 8, 10 -14). Among them, only a few transcription factors, such as JunB (but not the other Jun family members), were shown to be selectively activated in Th2 cells during differentiation by T cell receptor (TCR) engagement (11). The NFAT families of transcription factors, which encompass five evolutionary related proteins, play an important role in expression of many cytokine genes (15). Mature T cells express predominantly NFATp and NFATc, and both have been shown to activate the IL-4 gene in response to TCR stimulation (16, 17). Although NFATp and NFATc are expressed in both Th1 and Th2 cells, NFATp was shown to bind to the IL-4 enhancer and the IL-4 promoter only in stimulated Th2 cells, whereas the same transcription factor binds to the interferon (IFN)-␥ promoter only i...

show abstract

Control of Recent Thymic Emigrant Survival by Positive Selection Signals and Early Growth Response Gene 1

Cited by 20 publications

References 36 publications

Early growth response 2 regulates the survival of thymocytes during positive selection

Early growth response 2 regulates the survival of thymocytes during positive selection

Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes

Early Growth Response Protein-1 (Egr-1) Is Preferentially Expressed in T Helper Type 2 (Th2) Cells and Is Involved in Acute Transcription of the Th2 Cytokine Interleukin-4

Contact Info

Product

Resources

About