Defective homing and impaired induction of cytotoxic T cells by BCR/ABL-expressing dendritic cells.
Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from a hematopoietic stem cell expressing the BCR/ABL fusion protein. Leukemic and dendritic cells (DCs) develop from the same transformed hematopoietic progenitors. How BCR/ABL interferes with the immunoregulatory function of DCs in vivo is unknown. We analyzed the function of BCR/ABL-expressing DCs in a retroviral-induced murine CML model using the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen. BCR/ABL-expressing DCs were found in bone marrow, thymus, spleen, lymph nodes, and blood of CML mice. They were characterized by a low maturation status and induced only limited expansion of naive and memory cytotoxic T lymphocytes (CTLs). In addition, immunization with in vitro-generated BCR/ABL-expressing DCs induced lower frequencies of specific CTLs than immunization with control DCs. BCR/ABL-expressing DCs preferentially homed to the thymus, whereas only few BCR/ABL-expressing DCs reached the spleen. Our results indicate that BCR/ABL-expressing DCs do not efficiently induce CML-specific T-cell responses resulting from low DC maturation and impaired homing to secondary lymphoid organs. In addition, BCR/ABL-expressing DCs in the thymus may contribute to CML-specific tolerance induction of specific CTLs.
Mumprecht
Sabine
S
Department of Clinical Research, University of Berne, Berne, Switzerland.
Claus
Christina
C
Schürch
Christian
C
Pavelic
Viktor
V
Matter
Matthias S
MS
Ochsenbein
Adrian F
AF
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000502:physiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006023:Glycoproteins / Q000502:physiology*; D007114:Immunization; D007156:Immunologic Memory / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014916:Whole-Body Irradiation
D006023:Glycoproteins; D016044:Fusion Proteins, bcr-abl