GA binding protein regulates interleukin 7 receptor α-chain gene expression in T cells

Xue, Hai-Hui; Bollenbacher, Julie; Rovella, Valentina; Tripuraneni, Radhika; Du, Yang; Liu, Chengyu; Williams, Ann; McCoy, J. Philip; Leonard, Warren J.

doi:10.1038/ni1117

Cited by 123 publications

(182 citation statements)

References 46 publications

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“…Yet, the mechanism in CD4 ϩ T cells remains to be deciphered (9). Furthermore, the transcriptional factor GABP␣ has been shown to regulate IL-7R␣ expression in mouse T cells (19). In line with a previous study by Kim et al (24), we found no clear association between expression of IL-7R␣ and GFI-1 or GABP␣ in human lymphocytes, except a subtle increased in GFI-1 expression in naive CD8 ϩ T cells culture with IL-7 (data not shown).…”

Section: Discussionsupporting

confidence: 91%

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Alves

Leeuwen

Derks

et al. 2008

The Journal of Immunology

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IL-7Rα is essential for the development and homeostatic maintenance of mature T cells. Studies in humans and mice have shown that IL-7Rα expression is reduced by its cognate cytokine, IL-7, and Ag, suggesting that active regulation of IL-7 responsiveness is necessary to balance T cell numbers. We show that IL-7- or TCR/CD28-mediated signaling induced a rapid down-regulation of IL-7Rα expression on naive T cells on the mRNA and protein level, with a mild (10-fold) or strong (50-fold) gene suppression, respectively. In both situations, the down-regulation of IL-7Rα was blocked by cyclohexamide and actinomycin D, indicating the involvement of an active mechanism dependent on new transcription and protein synthesis. Upon IL-7 withdrawal, IL-7Rα mRNA and surface protein reappeared in a transcription-dependent manner within 7 h. Yet, IL-7Rα was hardly re-expressed during the same period after TCR/CD28-activation. Likewise, T cells that were activated through CMV in vivo did not re-express IL-7Rα after in vitro culture. Functionally, IL-7-induced down-regulation of IL-7Rα did not hinder the responsiveness of naive T cells to IL-7. Conversely, down-regulation of IL-7Rα on TCR/CD28-activated cells limited IL-7 responsiveness. Strikingly, ectopic expression of IL-7Rα cells on TCR/CD28-activated cells conferred a selective advantage in the response to IL-7. In conclusion, our data show that IL-7- and TCR/CD28-mediated signaling differentially regulate IL-7Rα expression on human T cells with a transient and chronic effect, respectively. The stringent and active regulation of IL-7Rα may constitute a homeostatic mechanism to curtail unwarranted T cell expansion.

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Section: Discussionsupporting

confidence: 91%

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Alves

Leeuwen

Derks

et al. 2008

The Journal of Immunology

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“…2C, bottom two bars). This result confirms previous findings that the Ets site is essential for activity of the Il7r promoter in T cells (23,30). In summary, these results show that the Ets binding site is required for activity of the Il7r promoter in both B and T cells.…”

Section: An Intact Ets Site Is Essential For Activity Of the Il7r Prosupporting

confidence: 93%

“…EYFP-positive cells were isolated by cell sorting 60 h after transfection, and gene expression in these cells were assessed by real-time PCR as previously described (23). For inducible RNA interference experiments, an oligonucleotide containing a previously described small interfering RNA (5Ј-AGAAGACAGA-AGTTCACCG-3Ј) (23) directed against the coding region of GABP␣ was adapted as a microRNA by ligation into the tetracycline-regulated retroviral vector SIN-TREmi30-PIG (TMP) (Open Biosystems, Huntsville, AL) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Regulation of the Interleukin-7 Receptor α Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells

DeKoter

Schweitzer

Kamath

et al. 2007

Journal of Biological Chemistry

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Signaling through the IL-7 receptor (IL-7R) is required for development and maintenance of the immune system. The receptor for IL-7 is heterodimeric, consisting of a common ␥ chain (␥c, encoded by Il2rg) and an ␣ subunit (IL-7R␣, encoded by Il7r). The Il7r gene is expressed specifically in the immune system in a developmental stage-specific manner. It is not known how the Il7r gene is transcriptionally regulated during B cell development. The goal of this study is to elucidate the function of the Il7r promoter region in developing B cells. Using a combination of 5 rapid amplification of cDNA ends analysis, transient transfection assays, and DNase I hypersensitivity mapping, we identified the location of the Il7r promoter. Using a combination of electrophoretic mobility shift analysis, chromatin immunoprecipitation experiments, and RNA interference experiments, we found that the Ets transcription factors PU.1 and GA-binding protein (GABP) activate the Il7r promoter by interacting with a highly conserved Ets binding site. In committed B lineage cells, GABP can promote Il7r transcription in the absence of PU.1. However, the results of retroviral gene transfer experiments suggest that PU.1 is uniquely required to initiate transcription of the Il7r locus at the earliest stages of progenitor B cell generation. In summary, these results suggest that Il7r transcription is regulated by both PU.1 and GABP in developing B cells. The cytokine interleukin-7 (IL-7)2 is essential for development and maintenance of the immune system (reviewed in Ref. 1). IL-7 is produced constitutively by stromal cells of the bone marrow, fetal liver, thymus, and by epithelial cells (2). IL-7 promotes both proliferation and differentiation of developing B and T lymphocytes (3, 4). The receptor for IL-7 (IL-7R, encoded by Il7r) is heterodimeric, consisting of an IL-7-specific ␣ chain (IL-7R␣) and a common ␥ chain (␥c, encoded by Il2rg), which is shared with other subunits comprising the receptors for IL-2, IL-4, IL-9, IL-15, and IL-21. The Il2rg gene is expressed by all hematopoietic cells (5). Transcription of the Il7r gene is initiated in common lymphoid progenitor cells (6). IL-7R␣ is expressed in developing B cells but is down-regulated upon B cell maturation (7,8). In developing T cells, IL-7R␣ is initially down-regulated at the CD4 and CD8 double negative 3 stage of thymic development (9). However, Il7r transcription is re-activated after the CD4 and CD8 double-positive stage and is expressed on peripheral CD4 or CD8 single-positive T cells (7). Therefore, the Il7r gene is expressed in a cell type and developmental stage-specific manner (7, 10). Targeted null mutation of either the Il7r (11, 12) or the Il2rg gene (13, 14) results in a profound block to early B and T cell development in mice. In human patients, mutations in the IL7RA gene cause a type of severe combined immunodeficiency in which the major deficiencies are in T cell development, whereas B and NK cells are relatively normal in number (15). Therefore, the IL-7R␣ is critically ...

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“…Levels of mRNA for the GA-binding protein and Stat5a, which are known to be involved in IL-7R expression and signaling (37,38), were higher in the splenic CD8 ϩ D b NP 366 ϩ set. A determining factor of CTL memory differentiation is the expression of IL-7R during the acute phase of infection (39).…”

Section: Discussionmentioning

confidence: 95%

Effector CD8⁺T cells recovered from an influenza pneumonia differentiate to a state of focused gene expression

Marshall

Olivas

Andreansky

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The restriction of influenza A virus replication to mouse respiratory epithelium means that this host response is anatomically compartmentalized, on the one hand, to sites of T cell stimulation and proliferation in the secondary lymphoid tissue and, on the other hand, to the site of effector T cell function and pathology in the pneumonic lung. Thus, it is hardly surprising that virus-specific CD8 ؉ T cells recovered by bronchoalveolar lavage (BAL) from the infected respiratory tract seem more ''activated'' in terms of both cytolytic activity and cytokine production than those cells isolated from the spleen. The present analysis uses Affymetrix microarray technology to compare profiles of gene expression in these two lineage-related, yet anatomically separate, lymphocyte populations. Ninety differentially expressed genes were identified for influenza-specific CD8 ؉ D b NP 366 ؉ T cells obtained directly ex vivo by BAL or spleen disruption, with nine genes being further analyzed by quantitative, real-time PCR at the population level. Integrin ␣E, for example, was shown by Affymetrix and real-time mRNA analyses and then by single-cell PCR and protein staining to be present at a much higher prevalence on the BAL CD8 ؉ D b NP366 ؉ set. The unpredicted finding, however, was that mRNA expression for 75% of the 90 genes was lower in T cells from the BAL than from the spleen. Apparently, the localization of virus-specific CD8 ؉ T cells to the site of virus-induced pathology is associated with a narrowing, or ''focusing,'' of gene expression that favors enhanced effector function in the damaged, ''high-antigen load'' environment of the pneumonic lung.Affymetrix gene array ͉ cytotoxic T cell ͉ influenza A virus ͉ viral immunology

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GA binding protein regulates interleukin 7 receptor α-chain gene expression in T cells

Cited by 123 publications

References 46 publications

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Regulation of the Interleukin-7 Receptor α Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells

Effector CD8⁺T cells recovered from an influenza pneumonia differentiate to a state of focused gene expression

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GA binding protein regulates interleukin 7 receptor α-chain gene expression in T cells

Cited by 123 publications

References 46 publications

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Differential Regulation of Human IL-7 Receptor α Expression by IL-7 and TCR Signaling

Regulation of the Interleukin-7 Receptor α Promoter by the Ets Transcription Factors PU.1 and GA-binding Protein in Developing B Cells

Effector CD8+T cells recovered from an influenza pneumonia differentiate to a state of focused gene expression

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Effector CD8⁺T cells recovered from an influenza pneumonia differentiate to a state of focused gene expression