In the adaptive immune system, crosstalk between B cells and T cells is pivotal to the expansion, differentiation, survival and effector functions of normal B cells in response to antigen. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+CD19+ B cells in the peripheral blood, secondary lymphoid organs and bone marrow of patients. Although the cellular origin of CLL cells is still a subject of debate, molecular profiling demonstrates that CLL cells share similar signatures with antigen-experienced memory B cells. In this regard, it is believed that T-cell-dependent mechanisms similar to those required during the normal maturation of B cells may also operate in CLL and contribute to disease progression. We recently demonstrated that the accumulation of clonal CD4+ T cells in CLL is associated with B-cell receptor (BCR) characteristics (mutation status and stereotypy), implicating specific T-cell crosstalk with CLL cells during tumor outgrowth. 1 This notion is further supported by the observation that so-called lymphoid proliferation centers, which are structural hallmarks in CLL, are composed of different antigen-presenting cells and numerous CD4+ T cells that are clustered together with activated CLL cells. 2 CLL activation in turn leads to enhanced viability, chemoresistance, and proliferation. Indeed, both in vitro and in vivo data demonstrate that activated CD4+ T cells provide stimuli, for example, CD40L, that drive CLL cells into proliferation. 3, 4 In addition, CD4+ T cells can protect CLL cells from spontaneous apoptosis in vitro. 5 As such, reversing the nature of CLL–T-cell interactions with immunomodulatory drugs is a therapeutic goal in CLL. 6, 7

To clarify the exact nature of CD4+ T cell help in the pathogenesis of CLL, we made use of GK5 mice (C57BL/6 background, hereafter referred to as GK mice), 8 which exhibit a complete loss of CD4+ T cells in the periphery (Supplementary Figure 1A) due to the expression of a CD4-targeting antibody, in conjunction with the TCL1-tg mouse (C57BL/6 background), which currently represents the best validated mouse model for human CLL, and has been shown to recapitulate some of the T-cell abnormalities associated with the disease. 9, 10 Established tumors derived from spleens of leukemic TCL1-tg mice were adoptively transferred intraperitoneally into GK recipients or their wild-type (WT) littermate controls to assess the impact of the loss of CD4+ cells on the outgrowth of established malignant clones. Surprisingly, CLL tumors developed faster in GK mice compared with WT