title: Lentiviral calnexin-modified dendritic cells promote expansion of high-avidity effector T cells with central memory phenotype.
abstract: Dendritic cells (DCs) are key immune mediators for the education and activation of effector cytotoxic T lymphocytes (CTLs). Ex vivo manipulation of DCs is an attractive strategy in immunotherapy. The chaperone proteins are known to hold the keys to proper protein folding and antigen processing. However, little is known of the role of molecular chaperones in DC and T-cell functions. We report that DCs expressing supraphysiological levels of calnexin, a chaperone protein, via lentiviral gene transfer stimulated the expansion of high-avidity CTLs with increased central memory phenotype. Microarray RNA profiling and analyses of protein expression with flow cytometry and multiplex enzyme-linked immunosorbent assay indicated that calnexin had a global effect on DCs with up-regulation of immune modulatory signals including costimulatory molecules, cytokines, chemokines and adhesion molecules. Compared with unmodified DCs, calnexin-DCs were capable of activating T cells to exhibit increased functional avidity associated with up-regulation of CCR7 and costimulatory tumour necrosis factor receptor superfamily molecules. These findings demonstrate a prominent role of calnexin in optimizing DC immunity with potential for improving immunotherapy.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, College of Medicine, Gainesville, FL, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Shuhong
authors.initials: S
authors.lastname: Han
authors.forename: Lily
authors.initials: L
authors.lastname: Lien
authors.forename: Lung-Ji
authors.initials: LJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D017951:Antigen Presentation / Q000276:immunology; D037281:Calnexin / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D049109:Cell Proliferation; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005822:Genetic Vectors; D007156:Immunologic Memory; D016130:Immunophenotyping; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D054400:Receptors, CCR7 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D019496:Cancer Vaccines; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D037281:Calnexin
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9571-6
references.pmid: 15980149
references.citation: J Immunol. 2005 Sep 15;175(6):3502-7
references.pmid: 16148092
references.citation: J Immunol. 2002 Feb 1;168(3):1167-71
references.pmid: 11801651
references.citation: Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4102-7
references.pmid: 8633023
references.citation: J Cell Sci. 2006 Feb 15;119(Pt 4):615-23
references.pmid: 16467570
references.citation: Annu Rev Immunol. 2008;26:421-52
references.pmid: 18303997
references.citation: Immunol Res. 2005;31(1):13-24
references.pmid: 15591619
references.citation: Immunity. 2004 Jan;20(1):17-23
references.pmid: 14738761
references.citation: Nat Rev Immunol. 2005 Apr;5(4):296-306
references.pmid: 15803149
references.citation: Nat Rev Immunol. 2006 May;6(5):383-93
references.pmid: 16622476
references.citation: J Immunol. 2005 May 15;174(10):5994-6004
references.pmid: 15879092
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6204-9
references.pmid: 11983911
references.citation: Science. 1996 Dec 6;274(5293):1613-4
references.pmid: 8984629
references.citation: J Immunol. 2000 Jan 1;164(1):191-200
references.pmid: 10605011
references.citation: Cell. 2001 Aug 10;106(3):255-8
references.pmid: 11509172
references.citation: Annu Rev Immunol. 2004;22:745-63
references.pmid: 15032595
references.citation: J Clin Oncol. 2004 Mar 15;22(6):1136-51
references.pmid: 15020616
references.citation: Mol Immunol. 2003 Jan;39(12):697-706
references.pmid: 12531281
references.citation: Curr Opin Cell Biol. 2005 Apr;17(2):210-5
references.pmid: 15780599
references.citation: J Immunother. 1999 Jul;22(4):288-98
references.pmid: 10404430
references.citation: Retrovirology. 2004 Nov 01;1:37
references.pmid: 15518595
references.citation: Mol Ther. 2008 Feb;16(2):269-79
references.pmid: 18071334
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9358-63
references.pmid: 12093915
references.citation: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4734-8
references.pmid: 1584811
references.citation: J Immunol. 1999 Jan 15;162(2):989-94
references.pmid: 9916724
references.citation: Curr HIV Res. 2003 Jul;1(3):287-94
references.pmid: 15046253
references.citation: Clin Cancer Res. 2005 Aug 1;11(15):5603-15
references.pmid: 16061879
references.citation: J Virol. 2004 Jan;78(1):206-15
references.pmid: 14671102
references.citation: Vaccine. 2006 Apr 24;24(17):3477-89
references.pmid: 16530303
references.citation: J Virol. 2002 Jul;76(14):7209-19
references.pmid: 12072520
references.citation: Nat Rev Mol Cell Biol. 2004 Oct;5(10):781-91
references.pmid: 15459659
references.citation: J Immunol Methods. 2001 Mar 1;249(1-2):99-110
references.pmid: 11226468
references.citation: J Immunol. 1999 Feb 15;162(4):2227-34
references.pmid: 9973498
references.citation: Immunol Rev. 2002 Aug;186:221-33
references.pmid: 12234374
references.citation: J Cell Biol. 1991 Mar;112(6):1099-115
references.pmid: 1999467
references.citation: Nat Biotechnol. 2002 Feb;20(2):143-8
references.pmid: 11821859
references.citation: Jpn J Hum Genet. 1992 Jun;37(2):149-50
references.pmid: 1327290
references.citation: J Immunol. 2001 Feb 1;166(3):1690-7
references.pmid: 11160212
references.citation: Mol Cell. 2004 Jan 16;13(1):125-35
references.pmid: 14731400