The role of IDO^high MDSCs in the microenvironment of CLL. Hematopoietic stem cells (HSCs) give rise to immature myeloid cells (IMCs). The latter may differentiate into myeloid-derived suppressor cells (MDSCs). CLL cells promote the generation of IDO^high MDSCs suppressing T-cell activation and proliferation. In addition, IDO^high MDSCs enhance the ability of CLL cells to promote conversion of naïve T cells into regulatory T cells (T_regs). T_regs in turn suppress the activity of cytotoxic CD8 T cells targeting CLL cells. Thus, MDSCs by multiple pathways promote CLL cell survival and suppression of the immune system. In addition, CLL cells are protected by direct interaction with stromal cells (eg, via CXCR4/CXCL12).