title: Alternative Ii-independent antigen-processing pathway in leukemic blasts involves TAP-dependent peptide loading of HLA class II complexes.
abstract: During HLA class II synthesis in antigen-presenting cells, the invariant chain (Ii) not only stabilizes HLA class II complexes in the endoplasmic reticulum, but also mediates their transport to specialized lysosomal antigen-loading compartments termed MIICs. This study explores an alternative HLA class II presentation pathway in leukemic blasts that involves proteasome and transporter associated with antigen processing (TAP)-dependent peptide loading. Although HLA-DR did associate with Ii, Ii silencing in the human class II-associated invariant chain peptide (CLIP)-negative KG-1 myeloid leukemic cell line did not affect total and plasma membrane expression levels of HLA-DR, as determined by western blotting and flow cytometry. Since HLA-DR expression does require peptide binding, we examined the role of endogenous antigen-processing machinery in HLA-DR presentation by CLIP(-) leukemic blasts. The suppression of proteasome and TAP function using various inhibitors resulted in decreased HLA-DR levels in both CLIP(-) KG-1 and ME-1 blasts. Simultaneous inhibition of TAP and Ii completely down-modulated the expression of HLA-DR, demonstrating that together these molecules form the key mediators of HLA class II antigen presentation in leukemic blasts. By the use of a proteasome- and TAP-dependent pathway for HLA class II antigen presentation, CLIP(-) leukemic blasts might be able to present a broad range of endogenous leukemia-associated peptides via HLA class II to activate leukemia-specific CD4(+) T cells.
authors.affiliation: Department of Hematology, Cancer Center Amsterdam, VU Institute for Cancer and Immunology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. m.luijn@vumc.nl
authors.forename: Marvin M
authors.initials: MM
authors.lastname: van Luijn
authors.forename: Martine E D
authors.initials: ME
authors.lastname: Chamuleau
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ostrand-Rosenberg
authors.forename: Yuri
authors.initials: Y
authors.lastname: Souwer
authors.forename: Adri
authors.initials: A
authors.lastname: Zevenbergen
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Arjan A
authors.initials: AA
authors.lastname: van de Loosdrecht
authors.forename: S Marieke
authors.initials: SM
authors.lastname: van Ham
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology*; D001752:Blast Crisis / Q000276:immunology*; D045744:Cell Line, Tumor; D006684:HLA-DR Antigens / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000944:Antigens, Differentiation, B-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C045084:invariant chain; C477327:transporter associated with antigen processing (TAP); D046988:Proteasome Endopeptidase Complex
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