Defective cross-presentation of viral antigens in GILT-free mice.
Gamma-interferon-inducible lysosomal thiolreductase (GILT) promotes major histocompatibility complex (MHC) class II-restricted presentation of exogenous antigens containing disulfide bonds. Here, we show that GILT also facilitates MHC class I-restricted recognition of such antigens by CD8+ T cells, or cross-presentation. GILT is essential for cross-presentation of a CD8+ T cell epitope of glycoprotein B (gB) from herpes simplex virus 1 (HSV-1) but not for its presentation by infected cells. Initiation of the gB-specific CD8+ T cell response during HSV-1 infection, or cross-priming, is highly GILT-dependent, as is initiation of the response to the envelope glycoproteins of influenza A virus. Efficient cross-presentation of disulfide-rich antigens requires a complex pathway involving GILT-mediated reduction, unfolding, and partial proteolysis, followed by translocation into the cytosol for proteasomal processing.
Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, Post Office Box 208011, New Haven, CT 06250-8011, USA.
Reshma
R
Singh
Peter
P
Cresswell
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D006367:HeLa Cells; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000276:immunology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000276:immunology* / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus; C477327:transporter associated with antigen processing (TAP); D010088:Oxidoreductases; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors; D046988:Proteasome Endopeptidase Complex