IFN-c Upregulates Survivin and Ifi202 Expression to Induce Survival and Proliferation of Tumor-Specific T Cells

Hdl Handle:
http://hdl.handle.net/10675.2/610
Title:
IFN-c Upregulates Survivin and Ifi202 Expression to Induce Survival and Proliferation of Tumor-Specific T Cells
Authors:
Zimmerman, Mary; Yang, Dafeng; Hu, Xiaolin; Liu, Feiyan; Singh, Nagendra; Browning, Darren; Ganapathy, Vadivel; Chandler, Phillip; Choubey, Divaker ( 0000-0002-6879-9109 ) ; Abrams, Scott I.; Liu, Kebin
Abstract:
Background: A common procedure in human cytotoxic T lymphocyte (CTL) adoptive transfer immunotherapy is to expand tumor-specific CTLs ex vivo using CD3 mAb prior to transfer. One of the major obstacles of CTL adoptive immunotherapy is a lack of CTL persistence in the tumor-bearing host after transfer. The aim of this study is to elucidate the molecular mechanisms underlying the effects of stimulation conditions on proliferation and survival of tumor-specific CTLs.; Methodology/Principal Findings: Tumor-specific CTLs were stimulated with either CD3 mAb or cognate Ag and analyzed for their proliferation and survival ex vivo and persistence in tumor-bearing mice. Although both Ag and CD3 mAb effectively induced the cytotoxic effecter molecules of the CTLs, we observed that Ag stimulation is essential for sustained CTL proliferation and survival. Further analysis revealed that Ag stimulation leads to greater proliferation rates and less apoptosis than CD3 mAb stimulation. Re-stimulation of the CD3 mAb-stimulated CTLs with Ag resulted in restored CTL proliferative potential, suggesting that CD3 mAb-induced loss of proliferative potential is reversible. Using DNA microarray technology, we identified that survivin and ifi202, two genes with known functions in T cell apoptosis and proliferation, are differentially induced between Ag- and CD3 mAb-stimulated CTLs. Analysis of the IFN-γ signaling pathway activation revealed that Ag stimulation resulted in rapid phosphorylation of STAT1 (pSTAT1), whereas CD3 mAb stimulation failed to activate STAT1. Chromatin immunoprecipitation revealed that pSTAT1 is associated with the promoters of both survivin and ifi202 in T cells and electrophoresis mobility shift assay indicated that pSTAT1 directly binds to the gamma activation sequence element in the survivin and ifi202 promoters. Finally, silencing ifi202 expression significantly decreased T cell proliferation.; Conclusions/Significance: Our findings delineate a new role of the IFN-γ signaling pathway in regulating T cell proliferation and apoptosis through upregulating survivin and ifi202 expression.
Citation:
PLoS One. 2010 Nov 22; 5(11):e14076
Issue Date:
22-Nov-2010
URI:
http://hdl.handle.net/10675.2/610
DOI:
10.1371/journal.pone.0014076
PubMed ID:
21124930
PubMed Central ID:
PMC2989915
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Biochemistry and Molecular Biology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorZimmerman, Maryen_US
dc.contributor.authorYang, Dafengen_US
dc.contributor.authorHu, Xiaolinen_US
dc.contributor.authorLiu, Feiyanen_US
dc.contributor.authorSingh, Nagendraen_US
dc.contributor.authorBrowning, Darrenen_US
dc.contributor.authorGanapathy, Vadivelen_US
dc.contributor.authorChandler, Phillipen_US
dc.contributor.authorChoubey, Divakeren_US
dc.contributor.authorAbrams, Scott I.en_US
dc.contributor.authorLiu, Kebinen_US
dc.date.accessioned2012-10-26T16:26:52Z-
dc.date.available2012-10-26T16:26:52Z-
dc.date.issued2010-11-22en_US
dc.identifier.citationPLoS One. 2010 Nov 22; 5(11):e14076en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid21124930en_US
dc.identifier.doi10.1371/journal.pone.0014076en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/610-
dc.description.abstractBackground: A common procedure in human cytotoxic T lymphocyte (CTL) adoptive transfer immunotherapy is to expand tumor-specific CTLs ex vivo using CD3 mAb prior to transfer. One of the major obstacles of CTL adoptive immunotherapy is a lack of CTL persistence in the tumor-bearing host after transfer. The aim of this study is to elucidate the molecular mechanisms underlying the effects of stimulation conditions on proliferation and survival of tumor-specific CTLs.en_US
dc.description.abstractMethodology/Principal Findings: Tumor-specific CTLs were stimulated with either CD3 mAb or cognate Ag and analyzed for their proliferation and survival ex vivo and persistence in tumor-bearing mice. Although both Ag and CD3 mAb effectively induced the cytotoxic effecter molecules of the CTLs, we observed that Ag stimulation is essential for sustained CTL proliferation and survival. Further analysis revealed that Ag stimulation leads to greater proliferation rates and less apoptosis than CD3 mAb stimulation. Re-stimulation of the CD3 mAb-stimulated CTLs with Ag resulted in restored CTL proliferative potential, suggesting that CD3 mAb-induced loss of proliferative potential is reversible. Using DNA microarray technology, we identified that survivin and ifi202, two genes with known functions in T cell apoptosis and proliferation, are differentially induced between Ag- and CD3 mAb-stimulated CTLs. Analysis of the IFN-γ signaling pathway activation revealed that Ag stimulation resulted in rapid phosphorylation of STAT1 (pSTAT1), whereas CD3 mAb stimulation failed to activate STAT1. Chromatin immunoprecipitation revealed that pSTAT1 is associated with the promoters of both survivin and ifi202 in T cells and electrophoresis mobility shift assay indicated that pSTAT1 directly binds to the gamma activation sequence element in the survivin and ifi202 promoters. Finally, silencing ifi202 expression significantly decreased T cell proliferation.en_US
dc.description.abstractConclusions/Significance: Our findings delineate a new role of the IFN-γ signaling pathway in regulating T cell proliferation and apoptosis through upregulating survivin and ifi202 expression.en_US
dc.rightsZimmerman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectImmunologyen_US
dc.subjectImmunology/Genetics of the Immune Systemen_US
dc.subjectImmunology/Immune Responseen_US
dc.subjectImmunology/Immunomodulationen_US
dc.subjectImmunology/Leukocyte Activationen_US
dc.subjectImmunology/Leukocyte Developmenten_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntibodies, Monoclonalen_US
dc.subject.meshAntigens, CD3en_US
dc.subject.meshApoptosisen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Proliferationen_US
dc.subject.meshCell Survivalen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Expression Profilingen_US
dc.subject.meshImmunotherapy, Adoptiveen_US
dc.subject.meshInhibitor of Apoptosis Proteinsen_US
dc.subject.meshInterferon-gammaen_US
dc.subject.meshIntracellular Signaling Peptides and Proteinsen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred BALB Cen_US
dc.subject.meshNeoplasms, Experimentalen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshRNA Interferenceen_US
dc.subject.meshReceptors, Interferonen_US
dc.subject.meshRepressor Proteinsen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshSTAT1 Transcription Factoren_US
dc.subject.meshT-Lymphocytes, Cytotoxicen_US
dc.subject.meshUp-Regulationen_US
dc.titleIFN-c Upregulates Survivin and Ifi202 Expression to Induce Survival and Proliferation of Tumor-Specific T Cellsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2989915en_US
dc.contributor.corporatenameDepartment of Biochemistry and Molecular Biology-
dc.contributor.corporatenameImmunotherapy Center-

Related articles on PubMed

All Items in Scholarly Commons are protected by copyright, with all rights reserved, unless otherwise indicated.