title: Effect of costimulation and the microenvironment on antigen presentation by leukemic cells.
abstract: Costimulatory signals supplied by genetically modified tumor cells can enable T-cell recognition of tumor-associated antigens that were previously silent when presented by unmodified tumor cells. Although the mechanism of the CD80/CD28 costimulation has been studied extensively in the normal T-cell/antigen-presenting cell (APC) interactions, it is unclear how expression of CD80 by tumor cells mediates its effect. We demonstrate here that optimal CD80 expression on a leukemic cell enhances T-cell recognition of alloantigen primarily by lowering the level of T-cell receptor (TCR) stimulation required for activation. CD80 expression by leukemic cells leads to increased survival of activated T cells by inducing upregulation of the antiapoptotic protein BCL-2, but not BCL-X(L). The cytokine microenvironment in which T cells are activated is crucial in determining their differentiation and consequently the nature of the immune response generated. Many tumor cells produce immunosuppressive cytokines that may not favor the induction of cell-mediated immunity. In this study, the presence of CD80 on leukemic cells increased T-cell activation in vitro, but this did not result in the production of Th1 cytokines. We show that this is due to a leukemia-derived soluble factor that inhibits the production of Th1 cytokines. Optimal expression of a costimulatory molecule, therefore, enhances the ability of leukemic cells to present antigen by amplifying TCR signals, but the microenvironment generated by leukemic cells may suppress the immune response required for their eradication. Thus, strategies aimed at inducing antileukemic immunity by providing leukemic cells with costimulatory functions must ensure the presence of an appropriate microenvironment.
authors.affiliation: Department of Haematological Medicine, King's College School of Medicine and Dentistry, London, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Buggins
authors.forename: N
authors.initials: N
authors.lastname: Lea
authors.forename: J
authors.initials: J
authors.lastname: Gäken
authors.forename: D
authors.initials: D
authors.lastname: Darling
authors.forename: F
authors.initials: F
authors.lastname: Farzaneh
authors.forename: G J
authors.initials: GJ
authors.lastname: Mufti
authors.forename: W J
authors.initials: WJ
authors.lastname: Hirst
mesh_terms: D017951:Antigen Presentation; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007938:Leukemia / Q000276:immunology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell