Cross-talk between CLL cells and the lymph node microenvironment. This figure displays the molecules involved in cross-talk between CLL cells and accessory cells in the lymphoid tissue microenvironments. Contact between CLL cells and nurselike cells (NLCs) is established and maintained by chemokine receptors and adhesion molecules. NLCs express the chemokines CXCL12 and CXCL13. NLCs attract CLL cells via the G protein–coupled chemokine receptors CXCR4 and CXCR5, which are expressed at high levels on CLL cells. NLCs also express the tumor necrosis factor family members BAFF and APRIL, providing survival signals to CLL cells via corresponding receptors (BCMA, TACI, BAFF-R). CD38 expression allows CLL cells to interact with CD31, the ligand for CD38, expressed by stromal and nurselike cells. Ligation of CD38 activates ZAP-70 and downstream survival pathways. Self and/or environmental antigens (Ags) are considered a key factor in stimulation and expansion of the CLL clone. Stimulation of the B-cell antigen receptor (BCR) complex (BCR and CD79a,b) induces downstream signaling by recruitment and activation of Syk and ZAP-70. BCR stimulation and coculture with NLC also induces CLL cells to secrete high levels of the chemokines CCL3 and CCL4, which are potent T cell–attracting chemokines. Through this mechanism, CLL cells can actively recruit T cells for cognate T-cell interactions with CLL cells. CD154⁺ T cells are preferentially found in CLL pseudofollicles and can interact with CLL cells via CD40. Cytokine secreted by T cells or CLL cells, such as IL-4 or tumor necrosis factor α, are considered important regulators of CLL cell survival. Collectively, this cross-talk between CLL cells and accessory cells results in activation of survival and drug resistance pathways, such as those provided by Bcl-2 and Mcl-1.