Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-γ by a T-bet-dependent mechanism
| Autor: | Aleix Gimeno, Stephen Devereux, Anna Parente-Ribes, Audun Os, Bjarne Bogen, Simone Bürgler, Ludvig A. Munthe, Geir E. Tjønnfjord, Dong Wang, Peter Jebsen |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Chemokine Chronic lymphocytic leukemia Immunology Cell CD38 Proinflammatory cytokine 03 medical and health sciences Interferon-gamma Mice 0302 clinical medicine Downregulation and upregulation immune system diseases Mice Inbred NOD hemic and lymphatic diseases medicine Immunology and Allergy Animals Humans neoplasms 030304 developmental biology Aged 0303 health sciences Immunity Cellular Membrane Glycoproteins biology Gene Expression Regulation Leukemic hemic and immune systems Middle Aged Th1 Cells medicine.disease ADP-ribosyl Cyclase 1 Leukemia Lymphocytic Chronic B-Cell Neoplasm Proteins Leukemia medicine.anatomical_structure biology.protein Cancer research Heterografts Cytokine secretion Female T-Box Domain Proteins Neoplasm Transplantation 030215 immunology |
| Zdroj: | Journal of immunology (Baltimore Md. : 1950) |
| ISSN: | 1550-6606 |
| Popis: | 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-bethiCD38hi 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. |
| Databáze: | OpenAIRE |
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