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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3339-3347.
Prepublished online as a Blood First Edition Paper on August 6, 2008; DOI 10.1182/blood-2008-01-134783.

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NEOPLASIA

Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3{alpha}

Björn Lamprecht1,2, Stephan Kreher1,2, Ioannis Anagnostopoulos3, Korinna Jöhrens3, Giovanni Monteleone4, Franziska Jundt1,2, Harald Stein3, Martin Janz1,2, Bernd Dörken1,2, and Stephan Mathas1,2

1 Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; 2 Hematology, Oncology and Tumorimmunology, Charité, Medical University Berlin, Berlin, Germany; 3 Institute for Pathology, Charité, Medical University Berlin, Berlin, Germany; and 4 Dipartimento di Medicina Interna e Centro di Eccellenza per lo Studio delle Malattie Complesse e Multifattoriali, Università Tor Vergata, Rome, Italy

The malignant Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (HL) are derived from mature B cells, but have lost a considerable part of the B cell–specific gene expression pattern. Consequences of such a lineage infidelity for lymphoma pathogenesis are currently not defined. Here, we report that HRS cells aberrantly express the common cytokine-receptor {gamma}-chain ({gamma}c) cytokine IL-21, which is usually restricted to a subset of CD4+ T cells, and the corresponding IL-21 receptor. We demonstrate that IL-21 activates STAT3 in HRS cells, up-regulates STAT3 target genes, and protects HRS cells from CD95 death receptor–induced apoptosis. Furthermore, IL-21 is involved in up-regulation of the CC chemokine macrophage-inflammatory protein-3{alpha} (MIP-3{alpha}) in HRS cells. MIP-3{alpha} in turn attracts CCR6+CD4+CD25+FoxP3+CD127lo regulatory T cells toward HRS cells, which might favor their immune escape. Together, these data support the concept that aberrant expression of B lineage–inappropriate genes plays an important role for the biology of HL tumor cells.


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D. Konforte, N. Simard, and C. J. Paige
IL-21: An Executor of B Cell Fate
J. Immunol., February 15, 2009; 182(4): 1781 - 1787.
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