Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5(+)CD19(+) B cells in the peripheral blood, and in primary and secondary lymphoid organs. A major complication associated with CLL is severe recurrent infections, which are often fatal. Vulnerability to infection is due to a wide variety of immunological defects, yet the initiating events of immunodeficiency in CLL are unclear. Using CLL patient samples and a mouse model of CLL, we have discovered that plasmacytoid dendritic cells (pDCs), which underpin the activity of effector immune cells critical for anti-viral immunity and anti-tumor responses, are reduced in number and functionally impaired in progressive CLL. As a result, the levels of interferon alpha (IFNα) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNα production was due to the decreased expression of FMS-like tyrosine kinase 3 receptor (Flt3) and Toll-like receptor 9 (TLR9), respectively. Reduced Flt3 expression was reversed using inhibitors of TGF-β and TNF, an effect correlating with a reduction in tumor load. Defects in pDC numbers and function offer new insight into mechanisms underpinning the profound immunodeficiency affecting CLL patients and provide a potentially novel avenue for restoring immunocompetency in CLL.
Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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Saulep-Easton
Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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Vincent
Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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Le Page
1] Department of Haematology, The Alfred Hospital, 55 Commercial Road, Melbourne, Victoria, Australia [2] Australian Centre for Blood Diseases, Division of Blood Cancers, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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Wei
1] Department of Haematology, The Alfred Hospital, 55 Commercial Road, Melbourne, Victoria, Australia [2] Australian Centre for Blood Diseases, Division of Blood Cancers, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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Ting
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH, USA.
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Croce
Department of Haematology, Peter MacCallum Cancer Centre, St. Andrews's Place, East Melbourne, Victoria, Australia.
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Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), 89 Commercial Road, Melbourne, Victoria, Australia.
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Mackay
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology*; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D016898:Interferon-alpha; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3