These CML-specific CTL were not detectable by tetramer staining probably due to their low numbers or

due to the downregulation of the TCR. However, CTL which resisted exhaustion were crucially involved in leukemia control and depletion of the CD8+ T cells by a monoclonal antibody led to rapid disease progression and death of the animals. These results indicate that although CML-specific CTL are present only at low frequency and functionally impaired in many effector functions when analyzed ex vivo, they are crucial effector cells in the TSA HDAC cell line control of CML. IL-7 is required for the long-term survival of naïve T cells in their quiescent state 28. IL-7-signaling mediates antiapoptotic effects on peripheral T cells by increasing Bcl-2 expression 8 and upregulating lung Kruppel-like factor 29. The regulation of IL-7 production is poorly understood. IL-7 production

seems to be constant and no upstream control sequences or inducible genes in the IL-7 region have been identified. On the contrary, IL-7Rα expression regulates the effects of IL-7 on target cells including CD8+ T cells 11. IL-7Rα is constitutively expressed on naïve T cells and is rapidly downregulated upon activation. In the presence of a persistent antigen stimulus like a chronic viral infection with LCMV in mice or with HIV or HCV in humans, the IL-7Rα remains downregulated 30–32. This correlated with reduced expression of Bcl-2 and Sorafenib ic50 with CTL exhaustion. In an acute infection, IL-7Rα is expressed only on a small fraction of effector CTL that do not die off during the contraction phase of the CTL response and give rise to memory T cells 10. In contrast to a chronic viral infection, in SSR128129E the presence of CML a large fraction of CTL retains IL-7Rα expression. Interestingly, the activation markers CD44 and PD-1 are coexpressed with IL-7Rα, indicating that in CML a large fraction of activated CTL retain IL-7Rα. This suggests that IL-7-mediated antiapoptotic effects prevent full exhaustion and physical deletion of the specific CTL. Of interest, malignant and normal granulocytes expressed IL-7.

In accordance with the hypothesis that IL-7 secretion is constant and not controlled by inducible genes, IL-7 mRNA of leukemic granulocytes and of control granulocytes was identical. The finding that granulocytes produce IL-7 was unexpected since so far, IL-7 secretion was only found in fetal liver cells, stromal cells in the bone marrow and thymus and in other epithelial cells 11. Therefore, in CML, the antigen-expressing granulocytes directly produce IL-7. Since the serum-level of IL-7 seems to be determined by consumption and by the availability of IL-7Rα-expressing target cells, the local production by CML-antigen expressing granulocytes in large numbers favors the persistence of IL-7Rα expressing CML-specific CTL. The maintenance of specific CTL by the leukemia seems counter-intuitive.