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.
Singh
Reshma
R
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.
Cresswell
Peter
P
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