The role of T cell costimulation by CD80 in the initiation and maintenance of the immune response to human leukemia.
Most human myeloid leukemias express both class I and class II HLA and it has been postulated that leukemia-associated peptides are presented by those molecules. It is possible, however, that leukemia cells escape the immune surveillance by lacking expression of "costimulatory" molecules required for activating the immune response. Human erythroleukemia line (HEL) has been the subject of previous detailed studies demonstrating surface expression of bona fide HLA molecules but inability to stimulate allogeneic response of proliferative or cytolytic T cells. We found that an HLA-DR+ subclone (HEL-DR+) expresses LFA-1, LFA-3, ICAM-1, ICAM-3, but neither CD80 nor CD86 on the surface. Transfection of CD80 cDNA into HEL-DR+ cells induced the allogeneic response of purified T cells from both cord blood and peripheral blood of adult donors, demonstrating that CD80 expression could lead to accessory cell-independent activation of naive T cells. Priming allogeneic peripheral blood T cells by HEL-DR+/CD80+ also lead to generation of cytotoxic T lymphocytes that lysed both HEL-DR+/CD80+ and wild type HEL-DR+ equally well, confirming CD80 expression is required only in the CTL induction phase but not in the CTL effector phase. We established and maintained alloproliferative T cell clones from adult blood by stimulation with the HEL-DR+/CD80+ line. The clones could respond not only to HEL-DR+/CD80+ line but also to the HEL-DR+ line; however, the proliferative response to HEL-DR+/CD80+ was amplified and sustained compared to the short-lived response to wild type HEL-DR+ cells. Therefore, expression of CD80 by HEL-DR+ cells was determinant both to initiate and sustain the T cell response. These experiments support the hypothesis that lack of expression of "costimulatory" molecules for T cells contributes to leukemia escape from immune surveillance, and provide preliminary data for the use of CD80 transfection in the immunotherapy of human leukemia.
Matsumoto
K
K
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Anasetti
C
C
D000328:Adult; D017951:Antigen Presentation; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen; D018968:CD58 Antigens / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000032:analysis; D005312:Fetal Blood / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D007114:Immunization; D007157:Immunologic Surveillance; D007167:Immunotherapy; D007231:Infant, Newborn; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D004915:Leukemia, Erythroblastic, Acute / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018968:CD58 Antigens; C497964:CD86 protein, human; D015815:Cell Adhesion Molecules; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C483616:ICAM3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1