Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3alpha.
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-3alpha (MIP-3alpha) in HRS cells. MIP-3alpha in turn attracts CCR6(+)CD4(+)CD25(+)FoxP3(+)CD127(lo) 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.
Lamprecht
Björn
B
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Kreher
Stephan
S
Anagnostopoulos
Ioannis
I
Jöhrens
Korinna
K
Monteleone
Giovanni
G
Jundt
Franziska
F
Stein
Harald
H
Janz
Martin
M
Dörken
Bernd
B
Mathas
Stephan
S
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D054418:Chemokine CCL20 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D019014:fas Receptor / Q000096:biosynthesis; D000098546:Interleukin-21
C108355:CCL20 protein, human; D054418:Chemokine CCL20; D015850:Interleukin-6; D007378:Interleukins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019014:fas Receptor; D000098546:Interleukin-21