Induction of MHC class I presentation of exogenous antigen by dendritic cells is controlled by CD4+ T cells engaging class II molecules in cholesterol-rich domains.
We investigated interactions between CD4+ T cells and dendritic cells (DC) necessary for presentation of exogenous Ag by DC to CD8+ T cells. CD4+ T cells responding to their cognate Ag presented by MHC class II molecules of DC were necessary for induction of CD8+ T cell responses to MHC class I-associated Ag, but their ability to do so depended on the manner in which class II-peptide complexes were formed. DC derived from short-term mouse bone marrow culture efficiently took up Ag encapsulated in IgG FcR-targeted liposomes and stimulated CD4+ T cell responses to Ag-derived peptides associated with class II molecules. This CD4+ T cell-DC interaction resulted in expression by the DC of complexes of class I molecules and peptides from the Ag delivered in liposomes and permitted expression of the activation marker CD69 and cytotoxic responses by naive CD8+ T cells. However, while free peptides in solution loaded onto DC class II molecules could stimulate IL-2 production by CD4+ T cells as efficiently as peptides derived from endocytosed Ag, they could not stimulate induction of cytotoxic responses by CD8+ T cells to Ag delivered in liposomes into the same DC. Signals requiring class II molecules loaded with endocytosed Ag, but not free peptide, were inhibited by methyl-beta-cyclodextrin, which depletes cell membrane cholesterol. CD4+ T cell signals thus require class II molecules in cholesterol-rich domains of DC for induction of CD8+ T cell responses to exogenous Ag by inducing DC to process this Ag for class I presentation.
Machy
Patrick
P
Centre d'Immunologie de Marseille-Luminy, 13288 Marseille, Cedex 9, France.
Serre
Karine
K
Baillet
Marjorie
M
Leserman
Lee
L
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D004527:Egg Proteins / Q000096:biosynthesis / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008563:Membrane Lipids / Q000037:antagonists & inhibitors / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D010047:Ovalbumin / Q000096:biosynthesis / Q000276:immunology; D010446:Peptide Fragments; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014407:Tumor Cells, Cultured; D047392:beta-Cyclodextrins
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D003505:Cyclodextrins; D004527:Egg Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008563:Membrane Lipids; D009097:Multienzyme Complexes; C110366:OVA-8; D010446:Peptide Fragments; D011961:Receptors, Fc; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D010047:Ovalbumin; D002784:Cholesterol; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex