title: IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells.
abstract: Chronic lymphocytic leukemia (CLL) cells multiply in secondary lymphoid tissue, but the mechanisms leading to their proliferation are still uncertain. In addition to B-cell receptor (BCR)-triggered signals, other microenvironmental factors might well be involved. In proliferation centers, leukemic B cells are in close contact with CD4(+)CD40L(+) T cells. Therefore, we here dissected the signals provided by autologous activated T cells (Tact) to CLL cells. Although the gene expression profile induced by Tact was highly similar to that induced by sole CD40 signaling, an obvious difference was that Tact induced proliferation of CLL cells. We determined that stimulation with only CD40L+IL-21 was sufficient to induce robust proliferation in CLL cells. We then defined an interleukin (IL)-21-induced gene signature in CLL, containing components of Janus kinase/signal transducer and activator of transcription and apoptosis pathways, and this signature could be detected in lymph node (LN) samples from patients. Finally, we could detect IL-21 RNA and protein in LN, and IL-21 production ex vivo by LN CD4(+)CXCR5(+) follicular helper T cells. These results indicate that in addition to BCR signaling, activated T cells might contribute to CLL cell proliferation via CD40 and IL-21. Targeting these signaling pathways might offer new venues for treatment of CLL.
authors.affiliation: Department of Experimental Immunology.
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Pascutti
authors.forename: Margot
authors.initials: M
authors.lastname: Jak
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tromp
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.forename: Ester B M
authors.initials: EB
authors.lastname: Remmerswaal
authors.forename: Rachel
authors.initials: R
authors.lastname: Thijssen
authors.forename: Martijn H A
authors.initials: MH
authors.lastname: van Attekum
authors.forename: Gregor G
authors.initials: GG
authors.lastname: van Bochove
authors.forename: Dieuwertje M
authors.initials: DM
authors.lastname: Luijks
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
authors.forename: René A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D053612:Janus Kinases / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D061251:Primary Cell Culture; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007378:Interleukins; D011947:Receptors, Antigen, B-Cell; D023201:CD40 Ligand; D053612:Janus Kinases; D000098546:Interleukin-21