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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901066v1 183/3/1838    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Hagn, M. Articles by Jahrsdörfer, B. PubMed PubMed Citation Articles by Hagn, M. Articles by Jahrsdörfer, B.

Human B Cells Secrete Granzyme B When Recognizing Viral Antigens in the Context of the Acute Phase Cytokine IL-21¹

Magdalena Hagn^*,, Elisabeth Schwesinger^2,*,, Verena Ebel^2,*,, Kai Sontheimer^2,*,, Julia Maier^*,, Thamara Beyer^*,, Tatiana Syrovets, Yves Laumonnier^,, Dorit Fabricius, Thomas Simmet and Bernd Jahrsdörfer^3,*,

^* Laboratory of Tumor and B Cell Immunology, Institute of Pharmacology of Natural Products and Clinical Pharmacology, and Department of Pediatrics, University of Ulm, Ulm, Germany; and Institute for Systemic Inflammation Research, University of Lubeck, Lubeck, Germany

Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19⁺CD20⁺CD27^–CD38^–IgD^– phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ B.J. is supported by Deutsche Forschungsgemeinschaft (German Research Foundation) Grant JA 1769/1-1, Deutsche Jose Carréras Leukämie-Stiftung (German Jose Carréras Leukemia Foundation) Grant SP 07/10, and Deutscher Akademischer Austauschdienst (German Academic Exchange Service) Grant D/08/11870.

² E.S.,V.E., and K.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Bernd Jahrsdörfer, Laboratory of Tumor and B Cell Immunology, Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstrasse 20, 89081 Ulm, Germany. E-mail address: bernd.jahrsdoerfer{at}uni-ulm.de

⁴ Abbreviations used in this paper: GrB, granzyme B; p, phosphorylated; P6, pyridone 6; TBEV, tick-borne encephalitis virus.

⁵ The online version of this article contains supplemental material.