title: Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-γ by a T-bet-dependent mechanism.
abstract: Chronic lymphocytic leukemia (CLL) is a B cell malignancy associated with increased levels of inflammatory cytokines. Similarly, expression of CD38 on CLL cells correlates with CLL cell survival and proliferation, but the mechanisms that regulate CD38 expression and inflammatory cytokines remain unclear. We have recently demonstrated that patients have CLL-specific Th cells that support CLL proliferation. In this article, we show that CLL cells attract such Th cells, thereby establishing an Ag-dependent collaboration. Blocking experiments performed in vitro as wells as in vivo, using a xenograft model, revealed that secretion of IFN-γ was a major mechanism by which CLL-specific Th cells increased CD38 on CLL cells. The expression of the transcription factor T-bet in peripheral blood CLL cells significantly correlated with CD38 expression, and transient transfection of CLL cells with T-bet resulted in T-bet(hi)CD38(hi) cells. Finally, chromatin immunoprecipitation experiments revealed that T-bet can bind to regulatory regions of the CD38 gene. These data suggest that CLL cells attract CLL-specific Th cells and initiate a positive feedback loop with upregulation of T-bet, CD38, and type 1 chemokines allowing further recruitment of Th cells and increased type 1 cytokine secretion. This insight provides a cellular and molecular mechanism that links the inflammatory signature observed in CLL pathogenesis with CD38 expression and aggressive disease and suggests that targeting the IFN-γ/IFN-γR/JAK/STAT/T-bet/CD38 pathway could play a role in the therapy of CLL.
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Department of Hematology, Oslo University Hospital, NO-0424 Oslo, Norway; Experimental Infectious Diseases and Cancer Research, University Children's Hospital Zürich, University of Zürich, CH-8008 Zurich, Switzerland; Simone.Buergler@kispi.uzh.ch ludvig@medisin.uio.no gtjonnfj@ous-hf.no.
authors.forename: Simone
authors.initials: S
authors.lastname: Bürgler
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Department of Hematology, Oslo University Hospital, NO-0424 Oslo, Norway;
authors.forename: Aleix
authors.initials: A
authors.lastname: Gimeno
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway;
authors.forename: Anna
authors.initials: A
authors.lastname: Parente-Ribes
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway;
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway;
authors.forename: Audun
authors.initials: A
authors.lastname: Os
authors.affiliation: Department of Hematological Medicine, King's College London, London SE5 9RS, United Kingdom;
authors.forename: Stephen
authors.initials: S
authors.lastname: Devereux
authors.affiliation: Department of Pathology, Oslo University Hospital, NO-0424 Oslo, Norway; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Jebsen
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway; K. G. Jebsen Centre for Influenza Vaccine Research, Department of Immunology, Oslo University Hospital, University of Oslo, NO-0424 Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
authors.affiliation: Department of Hematology, Oslo University Hospital, NO-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway; Simone.Buergler@kispi.uzh.ch ludvig@medisin.uio.no gtjonnfj@ous-hf.no.
authors.forename: Geir E
authors.initials: GE
authors.lastname: Tjønnfjord
authors.affiliation: Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, NO-0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, NO-0424 Oslo, Norway; Simone.Buergler@kispi.uzh.ch ludvig@medisin.uio.no gtjonnfj@ous-hf.no.
authors.forename: Ludvig A
authors.initials: LA
authors.lastname: Munthe
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology*; D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology*; D064593:Heterografts; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology*; D009368:Neoplasm Transplantation; D020825:T-Box Domain Proteins / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: C573415:IFNG protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1