Our results revealed that CML-specific CTL crucially contribute to disease control and are characterized by high IL-7Rα expression. Interestingly, CML cells produced IL-7 that was crucial for the

maintenance of specific CTL. Therefore, CML maintains Wnt inhibitor leukemia-specific CD8+ T-cell-mediated immunosurveillance by IL-7 signaling. Bone marrow was cotransduced with retroviral particles encoding for BCR/ABL and NUP98/HOXA9 and injected into irradiated syngeneic recipient mice. As shown previously, coexpression of BCR/ABL and NUP98/HOXA9 led to the development of CML and progression to blast crisis within several weeks 17. Granulocyte counts rose up to 9×107/mL (C57BL/6 control mice:<2×106 granulocytes/mL blood). Phenotypically, the leukemic cells consist of a population Y-27632 cost of immature myeloid blasts (MAC-1+,

GR-1+ and c-kit+) of up to 10% and a majority of mature granulocytes 17. This cotransduction was chosen to model the transition from chronic phase to blast crisis. To study antigen-specific immune responses, H8 transgenic mice were chosen as bone marrow donors. In this experimental setup, all leukemia cells expressed the immunodominant CTL epitope gp33 of lymphocytic choriomeningitis virus (LCMV) on MHC class I molecules as a model leukemia antigen (H8-CML mice). To analyze the impact of CD8+ T cells on disease progression, H8-CML mice with high granulocyte counts (>5×107 granulocytes/mL blood) were depleted of CD8+ TCL T cells by monoclonal antibody or were left untreated. Depletion of CD8+ T cells

led to disease progression and death of 83% of the animals within 4–19 days (Fig. 1A). CML progression was significantly slower in untreated control mice and 50% of the mice survived up to 75 days. On the contrary, treatment with IgG from rat serum (as control for αCD8 antibody YTS169.4) did not prolong survival when compared with untreated mice (Supporting Information Fig. 1). These results suggest that CD8+ T cells are crucially involved in the control of CML disease progression. The fact that a minority of the CD8+ T-cell-depleted animals still could control CML suggests that other effector mechanisms may contribute to the immunosurveillance of CML. In agreement with our earlier results, in CML mice no gp33-specific CTL response was detectable in the blood by tetramer staining 17. Naïve C57BL/6 mice and LCMV-immune mice which had been infected 8 wk previously with 200 pfu LCMV-WE were used as controls (Fig. 1B and D). The absence of specific CD8+ T cells in blood of CML mice by tetramer staining was in contrast to the rapid leukemia progression in CD8+ T-cell-depleted animals. Using a dextramer enrichment approach, we could detect gp33-specific CTL in pooled spleens and lymph nodes of H8-CML animals above the background of naïve C57BL/6 mice (Fig. 1C and D and Supporting Information Fig. 2A and B) 18.