1 Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5 þ CD19 þ 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 (IFNa) production, a cytokine critical for immunity, are markedly reduced. Lower pDC numbers with impaired IFNa 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-b 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. Leukemia advance online publication, 11 April 2014; doi:10.1038/leu.2014.105 KEY POINTS pDC numbers and IFNa production decrease with disease progression in CLL in a TNF-dependent manner. TNF or TGF-b inhibition restores pDC numbers in experimental CLL, offering a new strategy to improve immuno-competency in CLL. INTRODUCTION Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the developed world and is characterized by lymphocytosis with accumulation of B lymphocytes coexpressing CD5, CD19, CD20 and CD23, but with reduced expression of the surface B-cell receptor (BCR). 1–3 The majority of CLL patients present with indolent disease, which is often diagnosed via routine blood tests in asymptomatic individuals. As CLL is incurable and often with long progression-free survival (PFS) of 24 years or more, the current treatment strategy is to instigate therapy only upon symptomatic progression. 3–5 Although markers indicative of poor prognosis have been identified, such as expression of CD38, 6 unmutated immunoglobulin (Ig) variable heavy chain (IGV H) genes, 6 ZAP70 7 and TCL1, 8 there are still no clinical markers that predict when a patient with indolent CLL might evolve to disease progression requiring treatment. The EmTCL1-transgenic (Tg) mouse has emerged as a robust model for progressive CLL, sharing many features with the human disease. 9