Ex vivo priming of CD4 T cells converts immunological tolerance into effective antitumor immunity in a murine model of acute lymphoblastic leukemia.
Tumor escape mechanisms in leukemia are not well defined. To dissect immunological mechanisms responsible for immune tolerance toward leukemia, we established a murine model system allowing clonotypic analysis of leukemia-specific CD4 T cells recognizing ovalbumin (OVA). Upon i.v. injection of genetically engineered leukemia cells, dendritic cells (DCs) engulfed, processed and presented OVA to OVA-specific CD4 T cells. Consequently, leukemia-specific T cells were primed in vivo as shown by expression of activation markers and proliferative responses. However, in spite of detectable CD4 T cell responses in vitro and in vivo, no effective anti-leukemia immunity was established. In contrast, adoptively transferred DO11.10 T cells that were primed ex vivo mediated effective antitumor immunity. Furthermore, ex vivo primed DO11.10 T cells showed high expression of Th1 cytokines (interferon-gamma, tumor necrosis factor-alpha and interleukin-2) whereas in vivo primed OVA-specific CD4 T cells showed incomplete differentiation (proliferation without cytokine production). We conclude that activated T cells lacking effector function develop through incomplete differentiation in leukemia-bearing mice. Thus, priming conditions of leukemia-specific CD4 T cells critically determines the balance between immunity or tolerance toward leukemia.
Hegazy
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AN
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
Klein
C
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007109:Immunity / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007942:Leukemia, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007371:Interferon-gamma; D010047:Ovalbumin; D016044:Fusion Proteins, bcr-abl; D013936:Thymidine