Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1 Journal Article

   

Authors:	Romano, E.; Cotari, J. W.; da Silva, R. B.; Betts, B. C.; Chung, D. J.; Avogadri, F.; Fink, M. J.; St Angelo, E. T.; Mehrara, B.; Heller, G.; Münz, C.; Altan-Bonnet, G.; Young, J. W.
Article Title:	Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1
Abstract:	Human CD34 + progenitor-derived Langerhans-type dendritic cells (LCs) are more potent stimulators of T-cell immunity against tumor and viral antigens in vitro than are monocyte-derived DCs (moDCs). The exact mechanisms have remained elusive until now, however. LCs synthesize the highest amounts of IL-15R-α mRNA and protein, which binds IL-15 for presentation to responder lymphocytes, thereby signaling the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5). LCs electroporated with Wilms tumor 1 (WT1) mRNA achieve sufficiently sustained presentation of antigenic peptides, which together with IL-15R-α/IL-15, break tolerance against WT1 by stimulating robust autologous, WT1-specific cytolytic T-lymphocytes (CTLs). These CTLs develop from healthy persons after only 7 days' stimulation without exogenous cytokines and lyse MHC-restricted tumor targets, which include primary WT1 + leukemic blasts. In contrast, moDCs require exogenous rhuIL-15 to phosphorylate STAT5 and attain stimulatory capacity comparable to LCs. LCs therefore provide a more potent costimulatory cytokine milieu for T-cell activation than do moDCs, thus accounting for their superior stimulation of MHC-restricted Ag-specific CTLs without need for exogenous cytokines. These data support the use of mRNA-electroporated LCs, or moDCs supplemented with exogenous rhuIL-15, as vaccines for cancer immunotherapy to break tolerance against selfdifferentiation antigens shared by tumors. © 2012 by The American Society of Hematology.
Journal Title:	Blood
Volume:	119
Issue:	22
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2012-05-31
Start Page:	5182
End Page:	5190
Language:	English
DOI:	10.1182/blood-2011-09-382200
PROVIDER:	scopus
PMCID:	PMC3369609
PUBMED:	22510877
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84861849482&partnerID=40&md5=a03658e50daeec40243bb0d6b9af6dbf
Notes:	--- - "Export Date: 2 July 2012" - "CODEN: BLOOA" - "Source: Scopus"

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