Stimulation of B-CLL Cells with Interleukin 21 and Toll Like Receptor Agonists Induces a CTL-Like Transcriptional Profile

• Published in: Blood 2009-11, Vol.114 (22), p.3685-3685
• Main Authors: Hagn, Magdalena, Ebel, Verena, Sontheimer, Kai, Beyer, Thamara, Blackwell, Sue E., Simmet, Thomas, Weiner, George J., Jahrsdoerfer, Bernd
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V114.22.3685.3685

Abstract 3685 Poster Board III-621 Interleukin 21 (IL-21) and CpG oligodeoxynucleotides (CpG ODN) are two novel and highly promising agents for the treatment of hematological diseases. Recently, we reported that IL-21 and CpG ODN induce granzyme B (GrB) and GrB-dependent apoptosis in malignant B cells from patients with B chronic lymphocytic leukemia (B-CLL), but not in healthy peripheral B cells. Using various techniques including FACS analysis, Western immunoblotting and RT-PCR we further characterized the factors accountable for the different apoptotic response of B-CLL cells versus normal B cells. GrB induction in B-CLL cells after stimulation with IL-21 and CpG ODN was associated with upregulation of transcription factors, which are normally involved in the differentiation of cytotoxic T lymphocytes (CTL) including T-bet, Eomesodermin (EOMES) and nuclear factor of activated T cells (NFAT), a finding not observed in normal healthy B cells. Furthermore, the induction of GrB in B-CLL cells by IL-21 and CpG ODN required signaling via a JAK/STAT-dependent pathway, as suggested by simultaneous upregulation of phosphorylated STAT3 and complete abrogation of GrB expression by the pan-JAK inhibitor pyridone 6. Stimulation of B-CLL cells with IL-21 and CpG ODN upregulated molecules involved in cell adhesion (CD54), antigen presentation (MHC class I), co-stimulation (CD40, CD86), and GrB uptake (CD222), suggesting B-CLL cells activated with IL-21 and CpG ODN are able to contact other immune cells and may be able to reabsorb secreted GrB. Similar findings resulted when the toll-like receptor (TLR)7 agonist imiquimod was used instead of the TLR9 agonist CpG ODN, suggesting that comparable differentiation programs are initiated by TLR7 and TLR9. In summary, B-CLL cells can express transcription factors involved in cytotoxic differentiation of CTL as well as GrB in response to IL-21 and TLR stimulation. The B-CLL cell differentiation program described in this study could explain our recent findings of GrB-dependent apoptosis in B-CLL cells but not in benign B cells. Moreover, our data provide novel insights into the aberrant signaling state of B-CLL cells. No relevant conflicts of interest to declare.