Evidence for a role of CD28RE as a response element for distinct mitogenic T cell activation signals

Civil, Azem; Geerts, M.E.J.; Aarden, Lucien A.; Verweij, Cornelis L.

doi:10.1002/eji.1830221142

Cited by 36 publications

(27 citation statements)

References 24 publications

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“…This may represent differences unique to the system in which the experiments were performed; transcriptional upregulation of the IL-2 promoter by CD28 has been demonstrated in human Jurkat T-cell clones (2,3) and in human peripheral blood T cells (3,10), while the lack of a transcriptional effect has been obtained primarily from studies utilizing long-term murine T-cell clones (15,32). However, transcriptional activation by CD28 has been demonstrated in murine T cells from a transgenic mouse containing an AP-1 luciferase reporter (23).…”

Section: Discussionmentioning

confidence: 99%

CD28 Mediates Transcriptional Upregulation of the Interleukin-2 (IL-2) Promoter through a Composite Element Containing the CD28RE and NF-IL-2B AP-1 Sites

Shapiro

Truitt

Imboden

et al. 1997

Molecular and Cellular Biology

197

211

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Mutagenesis studies have demonstrated the requirement for the CD28-responsive element (CD28RE) within the interleukin-2 (IL-2) promoter for transcriptional upregulation by CD28. Here, we demonstrate that CD28 responsiveness is conferred by a composite element containing both the CD28RE and the NF-IL-2B AP-1 sites (RE/AP). Mutations at either site within the RE/AP composite element abolish activity. The RE/AP composite element is a site for signal integration within the IL-2 promoter, since its activation is dependent on at least two separate signalling pathways being activated, through the T-cell receptor, CD28, and/or phorbol myristate acetate. Activation is maximal when all three signals occur simultaneously. By using a panel of CD28 cytoplasmic domain mutants, it was found that the transcriptional activation of the RE/AP composite element correlates exactly with the pattern of IL-2 secretion induced by these mutants upon stimulation. Similar to the upregulation of IL-2 secretion, the transcriptional upregulation of the RE/AP composite element by CD28 is FK506 insensitive. The pattern of activation of the RE/AP composite element is different from that observed for either an NFAT or consensus AP-1 site, implying that RE/AP represents a unique element. Using gel shift analysis, we demonstrate that stimulation by CD28 induces the association of the NF-B family member c-Rel to the CD28RE within the RE/AP composite element. The transcriptional upregulation of IL-2 by CD28 appears, therefore, to be mediated through the RE/AP composite element, involving the association of c-Rel with the CD28RE.Activation of T cells by recognition of antigens and major histocompatibility complex products on the surfaces of antigen-presenting cells initiates a series of biochemical events leading to T-cell proliferation and cytokine secretion (33). Stimulation through the T-cell receptor (TCR) alone is insufficient for T-cell proliferation or interleukin-2 (IL-2) production. In the absence of costimulation, a state of unresponsiveness, termed anergy, may develop (13, 18). The failures to produce and respond to IL-2 are the major determinants of anergy. CD28, a 44-kDa glycoprotein expressed as a homodimer on most T cells, can mediate costimulation. Induction of anergy in T-cell clones was found to be blocked by activation of CD28 by monoclonal antibodies (7).One consequence of T-cell activation is the expression of IL-2, due to both transcriptional upregulation and stabilization of IL-2 mRNA. Transcriptional upregulation is mediated by the IL-2 promoter, contained within approximately 300 bp upstream from the transcriptional start site (reviewed in references 11 and 22). Engagement of CD28 enhances activation of the IL-2 promoter resulting from either TCR stimulation or use of phorbol esters such as phorbol myristate acetate (PMA). Mutagenesis studies have demonstrated that a CD28-responsive element (CD28RE), located within the IL-2 promoter between Ϫ160 and Ϫ152 relative to the transcriptional start site, is required for CD28-induced ...

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Section: Discussionmentioning

confidence: 99%

CD28 Mediates Transcriptional Upregulation of the Interleukin-2 (IL-2) Promoter through a Composite Element Containing the CD28RE and NF-IL-2B AP-1 Sites

Shapiro

Truitt

Imboden

et al. 1997

Molecular and Cellular Biology

197

211

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“…23,24 CD28-dependent intracellular signaling pathways finally lead to formation of the CD28-responsive complex, which is composed of members of the nuclear factor-B-Rel-family and binds to the CD28-responsive element (CD28RE) on the IL-2 promotor. 25,26 Ligands of the CD28 receptor and the main transmitters of costimulation are the members of the B7 family; two of them, B7-1 and B7-2, are well characterized, 22,27 but the existence of other costimulatory factors has been postulated. 28 Melanoma cells were found to synthesize or express only low levels of B7 molecules.…”

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confidence: 99%

Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells

et al. 2000

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Viral oncolysates of Newcastle disease virus (NDV) have been widely used for the treatment of malignant melanoma. Apparently, this nononcogenic and apathogenic paramyxovirus can alter the immunogenicity of tumor cells. To determine the influence of NDV infection on a tumor-specific T-cell response on a functional level, we used autologous primary melanoma cells infected with the NDV-strain Ulster. Therefore, melanoma cells and tumor-infiltrating lymphocytes were prepared from a freshly resected tumor, and tumor-infiltrating lymphocytes were subjected to limited dilution cloning. Proliferation assays of the T-helper cell clone sTS3 (CD4 ϩ )showed that the T-cell clone was rendered nonreactive against its autologous major histocompatibility complex II ϩ , B7-1/B7-2 Ϫ melanoma SMS, even remaining unresponsive to subsequent stimulation by interleukin-2. NDV infection of the SMS melanoma cell line not only completely restored the proliferative response of sTS3 to SMS, comparable with stimulation by cross-linking of anti-CD3/anti-CD28 monoclonal antibodies, but also inhibited the induction of anergy. Electrophoretic mobility shift assays of sTS3 cell lysates revealed the induction of the CD28-responsive complex by coincubation with NDV-infected melanoma cells. Because the induction of this complex of nuclear proteins shows specificity for the activation of the CD28 pathway but functional B7-1/B7-2 expression was not detectable on SMS melanoma cells at any timepoint, we propose the induction of a costimulatory factor different from B7 by NDV viral proteins. Cancer Gene Therapy (2000) 7, 316 -323

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“…The CD28RE was originally defined as a major and unique response element for the CD28-B7-1 signal transduction pathway (18). However, recent data suggest that induction of binding of nuclear proteins to the CD28RE is not exclusive to the CD28 pathway (12). The AP-1 transcription factor is a complex composed of proteins belonging to the Jun and Fos families.…”

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confidence: 99%

Costimulation by B7-1 and LFA-3 Targets Distinct Nuclear Factors That Bind to the Interleukin-2 Promoter: B7-1 Negatively Regulates LFA-3-Induced NF-AT DNA Binding

Parra

Varga

Hedlund

et al. 1997

Molecular and Cellular Biology

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We have characterized the regulation of nuclear factors involved in transcriptional control of the interleukin-2 (IL-2) promoter-enhancer activity in Jurkat T cells stimulated with superantigen presented on HLA-DR transfectants combined with the ligands LFA-3 (CD58) and B7-1 (CD80). Gel shift analyses showed that NF-AT was strongly induced in LFA-3-costimulated Jurkat T cells, suggesting that NF-AT is a key target nuclear factor for the CD2-LFA-3 pathway. Studies using HLA-DR-B7-1-LFA-3 triple transfectants showed that the LFA-3-induced NF-AT DNA binding activity was negatively regulated by B7-1 costimulation. In contrast, induction of a CD28 response complex containing only c-Rel proteins was seen after B7-1 costimulation. Both LFA-3 costimulation and B7-1 costimulation induced the AP-1 and NF-B nuclear factors. Distinct compositions of the NF-AT complexes were seen in B7-1-and LFA-3-costimulated cells. LFA-3 induced primarily Jun-D, Fra-1, and Fra-2, while B7-1 induced June-D-Fos complexes. In contrast, AP-1 and NF-B complexes induced in B7-1-and LFA-3-costimulated T cells showed similar contents. Transient transfection of Jurkat T cells with a construct encoding the IL-2 enhancer-promoter region (position ؊500 to ؉60) linked to a luciferase reporter gene revealed that B7-1 costimulation was required to induce strong transcriptional activity. Combined B7-1-LFA-3 costimulation resulted in a synergistic increase in IL-2 transcriptional activity. Multimers of the AP-1, NF-AT, NF-B, and CD28 response elements showed distinct kinetics and activity after LFA-3 and B7-1 costimulation and revealed that B7-1 and LFA-3 converge to superinduce transcriptional activity of the AP-1, NF-AT, and CD28 response elements. Transcriptional studies with an IL-2 enhancerpromoter carrying a mutation in the CD28 response element site revealed that the activity was reduced by 80% after B7-1 and B7-1-LFA-3 costimulation whereas the transcriptional activity induced by LFA-3 was unaffected. Our data strongly suggest a selectivity in induction of nuclear factors by the CD2-LFA-3 and CD28-B7-1 pathways. This selectivity may contribute to regulation of the levels of IL-2 induced by LFA-3 and B7-1 costimulation and favor autocrine and paracrine T-cell responses, respectively.

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Evidence for a role of CD28RE as a response element for distinct mitogenic T cell activation signals

Cited by 36 publications

References 24 publications

CD28 Mediates Transcriptional Upregulation of the Interleukin-2 (IL-2) Promoter through a Composite Element Containing the CD28RE and NF-IL-2B AP-1 Sites

CD28 Mediates Transcriptional Upregulation of the Interleukin-2 (IL-2) Promoter through a Composite Element Containing the CD28RE and NF-IL-2B AP-1 Sites

Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells

Costimulation by B7-1 and LFA-3 Targets Distinct Nuclear Factors That Bind to the Interleukin-2 Promoter: B7-1 Negatively Regulates LFA-3-Induced NF-AT DNA Binding

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