Th17 cell cross talk with CLL microenvironment. Th17 cell differentiation is promoted in CLL via augmented levels of differentiation cytokines, including IL-6, IL-23, and IL-1β. Homotypic CD5 interactions between naïve CD4⁺ T cells and CLL cells might also promote IL-23R expression and drive Th17 cell programming. A negative correlation exists between Th17 cells and CD38/ZAP-70 expression in CLL cells, and ex vivo monoclonal antibody blocking of CD38 increased Th17 cell proportions through killing CLL cells in patient PBMCs. CLL Th17 cells secrete high levels of IL-17A that might perform direct or indirect cytotoxic activity on CLL cells via interaction with IL-17RA. Activated CLL cells can increase miR-155 expression in Th17 cells, leading to increased IL-17F production, which can activate NF-κB signaling in CD8⁺ T cells, leading to increased cytotoxic potential. Antileukemic activity of CLL Th17 cells might include IFN-γ production and/or recruitment of cytotoxic iNKT- and IL-17–producing CD8⁺ T (Tc17) cells. In contrast, increased CD39⁺ Tregs in CLL with enhanced Tim-3/Galectin-9 (Gal-9) signaling can have immunosuppressive effects through the release of IL-10, which is also produced by CLL cells and can act on IL-10Rs expressed by Th17 cells. CLL-derived PMN-MDSCs can promote IL-17F production by Th17 cells, which might influence disease progression. Furthermore, cells of myeloid origin including mature granulocytes and mast cells can release IL-17A within CLL microenvironment, which might promote granulocyte colony stimulating factor (G-CSF) production and granulopoiesis for supporting CLL cell survival. Finally, IL-17A can promote IL-6 production by BMMSCs, which helps support CLL cell proliferation.