Figure 5.

Representative view of the iNKT/innate CD8(+) T-cell axis hypothesis in chronic myeloid leukemia (CML). We propose the following scenario in CML: (A) steady state/healthy situation. Normal hematopoietic stem cells (HSC) generate normal immune cells. Antigens are presented via the CD1d molecule by dendritic cells (DCs) to iNKT cells. We propose that activated iNKT cells produce IL-4 but the possibility of a T-cell receptor (TCR)-independent mechanism for IL-4 secretion cannot be ruled out. IL-4 is thought to take part with IL-15 in the development/homeostasis of innate CD8(+) T cells. iNKT and innate CD8(+) T cells produce IFN-γ and perforin in response to the innate-like IL-12 + IL-18 stimulation. (B) Chronic phase of CML. Leukemic stem cells (LSC) produce modified immune cells bearing BCR–ABL translocation, including DCs. Impaired CD1d antigen presentation by DCs results from activation of the Rho/Rock pathway via the DH-PH domain of the ABL part of BCR–ABL. iNKT cell development/stimulation is thereby impaired, especially in terms of promyelocytic leukemia zinc-finger factor (PLZF) expression and IL-4 production. Consequently, we surmise that the innate CD8(+) T subset is defective in number and function. (C) Restoration of the iNKT/innate CD8(+) T-cell axis by therapies. IFN-α therapy is thought to help restoring DCs and innate CD8(+) T cells as well as other unidentified cells. Tyrosine kinase inhibitor (TKI) therapies targeting the ABL tyrosine kinase domain clear/control the generation of LSC and abnormal immune cells, including DCs. Fasudil therapy, combined with TKI, restores the CD1d presentation by DCs to iNKT cells and is one possible mechanism to restore the iNKT/innate CD8(+) T-cell axis.