Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling Journal Article

  

Authors:	Nishikawa, H.; Kato, T.; Hirayama, M.; Orito, Y.; Sato, E.; Harada, N.; Gnjatic, S.; Old, L. J.; Shiku, H.
Article Title:	Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling
Abstract:	We previously found that a Salmonella typhimurium vector engineered to secrete soluble tumor antigen induces CD4+ T cells resistant to CD4+CD25+ regulatory T cells (Treg) and that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) signal is involved in the development of this resistance. In this study, we address the potential of incorporating GITR ligand (GITRL) as a way to augment the immunogenicity of cancer vaccines. BALB/c mice were immunized by gene gun with plasmids encoding the mutated extracellular signal-regulated kinase 2 (mERK) with or without plasmids encoding mouse GITRL. Coadministration with GITRL during primary and secondary immunization enhanced the induction of mERK-specific CD8+ T cells. Antibody depletion and minigene analysis suggested that GITRL directly activated CTL epitope-specific CD8+ T cells independently of CD4+ T cells. Immunization with plasmids encoding a CTL epitope and GITRL resulted in strong tumor inhibition in a CD8+ T cell-dependent manner. Furthermore, CTL epitope-specific CD8+ T cells induced by immunization with plasmids encoding CTL epitope coadministered with GITRL were refractory to suppression by CD4 +CD25+ Tregs compared with CD8+ T cells induced without GITR signaling. We propose that coadministration of GITR signaling agents with tumor antigens constitutes a promising novel strategy for cancer vaccine development. ©2008 American Association for Cancer Research.
Keywords:	signal transduction; controlled study; gene mutation; nonhuman; genetic analysis; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; cytology; metabolism; animals; mice; biological model; models, biological; animal experiment; animal model; mice, inbred balb c; gene vector; genetic vectors; cancer inhibition; cd4+ cd25+ t lymphocyte; regulatory t lymphocyte; biosynthesis; chemistry; bagg albino mouse; antigen specificity; t-lymphocytes, regulatory; immunogenicity; epitope; plasmid; mitogen activated protein kinase 1; glucocorticoid; plasmids; tumor growth; glucocorticoid induced tumor necrosis factor receptor; interleukin 2 receptor alpha; interleukin-2 receptor alpha subunit; tumor necrosis factor; glucocorticoids; plasmid dna; immunization; epitopes; mitogen-activated protein kinase 1; gene gun; tumor necrosis factors
Journal Title:	Cancer Research
Volume:	68
Issue:	14
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2008-07-15
Start Page:	5948
End Page:	5954
Language:	English
DOI:	10.1158/0008-5472.can-07-5839
PUBMED:	18632650
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-48649083285&partnerID=40&md5=8dfd06f624e0f63e82aeb00376d11fbc
Notes:	--- - "Cited By (since 1996): 18" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus"

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