Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease with a characteristic chronic phase (cp) of several years before progression to blast crisis (bc). The immune system may contribute to disease control in CML. We analyzed leukemia-specific immune responses in cpCML and bcCML in a retroviral-induced murine CML model. In the presence of cpCML and bcCML expressing the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen, leukemia-specific cytotoxic T lymphocytes (CTLs) became exhausted. They maintained only limited cytotoxic activity, and did not produce interferon-␥ or tumor necrosis factor-␣ or expand after restimulation. CML-specific CTLs were characterized by high expression of programmed death 1 (PD-1), whereas CML cells expressed PD-ligand 1 (PD-L1). Blocking the PD-1/PD-L1 interaction by generating bcCML in PD-1-deficient mice or by repetitive administration of ␣PD-L1 antibody prolonged survival. In addition, we found that PD-1 is up-regulated on CD8 ؉ T cells from CML patients. Taken IntroductionChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. 1 The disease is bi-or triphasic, comprising a chronic, an accelerated, and a terminal blast phase in which the patients develop an acute leukemia of either myeloid (AML) or, less often, lymphoid (ALL) cell type. More than 90% of all CML cases are associated with the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 forming the breakpoint cluster region/ Abelson protein tyrosine kinase (BCR/ABL) fusion protein, a constitutively activated tyrosine kinase. 2,3 Depending on the precise breakpoints in the BCR gene, different forms of BCR/ABL fusion protein with different molecular weights can be generated (p190BCR/ABL, p210BCR/ABL, and p230BCR/ABL). CML patients predominantly express p210BCR/ABL. 1 Currently, BCR/ABL-selective tyrosine kinase inhibitors are the standard treatment for CML. However, resistant clones often develop during treatment. At present, the only curative treatment for CML is allogeneic hematopoietic stem cell transplantation. 4 Several earlier studies suggested that the immune system plays an important role in the control of CML. CML cells are susceptible to lysis by CD8 ϩ T cells 5 and natural killer (NK) cells in vitro. 6 For unknown reasons, CML is the most graft-versus-leukemiasensitive leukemia. 7 In addition, cytotoxic T lymphocytes (CTLs) directed against leukemia antigens are found in CML patients without hematopoietic stem cell transplantation, including CTLs specific for BCR/ABL, overexpressed self-proteins such as proteinase-3, and Wilms tumor 1 protein. 5,8 However, the physiologic relevance of these leukemia-specific CTL responses in the control of CML is unknown. The presence of CTL escape mechanisms during CML disease progression to blast crisis suggests that CTLs are involved in the control of the chronic phase of the disease. ...

Different viruses elicit distinct phenotypes of memory cytotoxic T lymphocytes (CTL). This is reflected in differential expression of homing receptors and costimulatory molecules like CD27. Memory CTL retained CD27 following lymphocytic choriomeningitis virus (LCMV) infection, but not after immunization with recombinant vaccinia virus or tumor cells expressing LCMV glycoprotein. Stable CD27 expression on memory CTL required ligation by CD70 expressed on polyclonally activated B cells during the contraction phase. The functional consequence of CD27 expressed on virus-specific CTL was analyzed in CD27-deficient mice. LCMV infection of CD27 -/-mice revealed that primary CTL activation and expansion as well as elimination of the virus were independent of CD27 expression. In contrast, ligation of CD27 on memory CTL upon secondary antigen encounter increased clonal expansion and improved protection against re-infection. This points to novel B cell-CTL interactions during viral infection and to a beneficial role of polyclonal B cell activation that represents a characteristic of murine LCMV, human immunodeficiency virus and human hepatitis B and C virus infection.

IntroductionImatinib mesylate (STI571, Glivec; Novartis Pharma AG, Basel, Switzerland) selectively inhibits the tyrosine kinases (TKs) ABL, BCR/ABL, ARG, PDGF-R ␣ and ␤, and c-KIT. Constitutive activation of these TKs has been documented in chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph ϩ ) acute lymphocytic leukemia, myeloproliferative disorders due to chromosomal rearrangements in PDGF-R, and gastrointestinal stromal tumors with mutations in c-KIT. [1][2][3][4] In these diseases, blocking of TKs with imatinib is very efficient and substantially improves clinical outcome.Since TKs are involved in various intracellular signaling pathways, it is not surprising that imatinib treatment affects immune responses. Clinical observations have suggested that imatinib treatment correlates with a reversible dose-dependent lymphopenia and hypogammaglobulinemia. 5 Experimental in vitro studies have demonstrated that imatinib inhibited the development of human CD34 ϩ progenitor cell-derived dendritic cells (DCs). In addition, DCs exposed to imatinib were less potent in inducing cytotoxic T-cell (CTL) responses against tumor and recall antigens. 6 However, results of the effect of imatinib on DC maturation are controversial. Other experiments have suggested a normal maturation but reduced expansion of DCs in mice when stimulated with Flt3L. 7 Further, it has been shown that treating DCs in vitro with imatinib enhanced antigen-presenting cell function and overcame tumor-induced CD4 ϩ T-cell tolerance. 8 In addition, several in vitro studies using T cells isolated from human peripheral blood have demonstrated a dose-dependent reduction of T-cell proliferation in the presence of imatinib. 1,9,10 These results raise the possibility that imatinib could affect normal immune functions through TK inhibition. TKs play a prominent role in T-cell receptor (TCR) and B-cell receptor (BCR) signal transduction, and, thus, it is conceivable that imatinib may interfere with this process. TCR ligation triggers a signaling cascade that includes activation of the TKs Lck, ZAP70, and Ltk. A recent study has reported the requirement of c-ABL and ARG TKs for TCR-dependent transcriptional activation. 11 c-ABL is activated by Lck and then leads to the phosphorylation of ZAP70. It remains unclear whether c-ABL activates only ZAP70 or also activates other downstream proteins. 12 However, primary T cells lacking functional ABL TKs showed decreased IL-2 production and cell proliferation in response to TCR stimulation. 11 Comparably, it has been shown that ABL phosphorylates the BCR coreceptor CD19, suggesting a role for ABL in the regulation of B-cell proliferation. 13 Taken together, these experiments suggest that imatinib treatment in vivo may crucially influence antiviral CD8 ϩ T-and B-cell responses. However, physiologic consequences of imatinib treatment on protective immune response have not yet been demonstrated.Primary infection with lymphocytic choriomeningitis virus (LCMV), a noncytopathic RNA virus, is controlled almost ex...

Chronic myelogenous leukemia (CML) is IntroductionChronic myelogenous leukemia (CML) is a malignant clonal myeloproliferative disease. The BCR/ABL fusion protein results from the reciprocal chromosomal translocation t(9;22) forming the Philadelphia chromosome (Ph). BCR/ABL is responsible for the malignant phenotype of leukemic cells in CML and increases cell proliferation, inhibits apoptotic processes, and alters cellular adhesion of myeloid cells. 1,2 CML is characterized by an initial chronic phase with a massive expansion of all stages of the granulocyte cell lineage. Eventually, hematopoietic differentiation becomes arrested and CML progresses to blast crisis with immature blast cells accumulating in the periphery. 1 Several studies have shown that cytotoxic T lymphocytes (CTLs) are involved in the immunosurveillance of CML. BCR/ ABL is a leukemia-specific antigen, and CTLs specific for peptides derived from its sequence could recognize CML cells in vitro and in vivo. 3,4 This suggests that there is efficient intracellular processing and presentation of BCR/ABL-derived peptides by CML cells. In addition, overexpressed self-proteins, such as proteinase-3, Wilms tumor 1 protein, and minor histocompatibility antigens, can act as leukemia-specific antigens for T cells. 5 Dendritic cells (DCs) are professional antigen-presenting cells and are key mediators for the initiation and regulation of both innate and adaptive immune responses. 6 DCs are a heterogeneous population that can be divided into myeloid and plasmacytoid DCs based on their origin, expression of surface markers, and function. 7 As CML mainly affects cells of the myeloid lineage, it is probable that myeloid BCR/ABL-expressing DCs are circulating in CML patients. Indeed, BCR/ABL-expressing DCs could be detected in the peripheral blood of CML patients. 7,8 However, CML patients in chronic phase had reduced numbers of circulating myeloid and plasmacytoid DCs compared with healthy persons. 9,10 Contradictory data regarding the maturation status and function of BCR/ABLexpressing DCs have been published. BCR/ABL-expressing DCs had either a normal maturation status or lower expression of the costimulatory molecules CD80/CD83/CD40 compared with control DCs. 7,8,11,12 In acute myeloid leukemia, the plasmacytoid DCs were immature and could not elicit the proliferation of naive CD4 ϩ T cells. 13 Moreover, in vitro-generated BCR/ABL-expressing DCs have been reported to be defective in antigen processing. 7,11 In contrast, other studies suggested that BCR/ABL-expressing DCs are able to effectively stimulate the proliferation of allogeneic and autologous T cells. 8,14 Similarly, vaccination with autologous, nonirradiated leukemic DCs induced antileukemic T-cell responses in some CML patients. 15 The function of BCR/ABL-expressing DCs in vivo is unknown. Therefore, we analyzed the function of BCR/ABL-expressing DCs in a murine retroviral-induced bone marrow transduction and transplantation model. 16 To study antigen-specific immune responses, we used H8 transgenic...