Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10.
Virally infected cells degrade intracellular viral proteins proteolytically and present the resulting peptides in association with major histocompatibility complex (MHC) class I molecules to CD8+ cytotoxic T lymphocytes (CTLs). These cells are normally prone to CTL-mediated elimination. However, several viruses have evolved strategies to avoid detection by the immune system that interfere with the pathway of antigen presentation. Epstein-Barr virus (EBV) expresses a predominantly late protein, the BCRF1 gene product vIL-10, that is similar in sequence to the human interleukin-10 (hIL-10). We show here that vIL-10 affects the expression of one of the two transporter proteins (TAPs) associated with antigen presentation. Similarly, hIL-10 showed the same activity. Expression of the LMP2 and TAP1 genes but not expression of TAP2 or LMP7 is efficiently downregulated, indicating a specific IL-10 effect on the two divergently transcribed TAP1 and LMP2 genes. Downregulation of TAP1 by IL-10 hampers the transport of peptide antigens into the endoplasmatic reticulum, as shown in the TAP-specific peptide transporter assay, their loading onto empty MHC I molecules, and the subsequent translocation to the cell surface. As a consequence, IL-10 causes a general reduction of surface MHC I molecules on B lymphocytes that might also affect the recognition of EBV-infected cells by cytotoxic T cells.
Zeidler
R
R
GSF-National Research Center for Environment and Health, Institut für Klinische Molekularbiologie und Tumorgenetik, München, Germany.
Eissner
G
G
Meissner
P
P
Uebel
S
S
Tampé
R
R
Lazis
S
S
Hammerschmidt
W
W
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D001402:B-Lymphocytes / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003546:Cysteine Endopeptidases; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D004854:Herpesvirus 4, Human; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000502:physiology*; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000502:physiology*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; C066460:BCRF1 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016326:Extracellular Matrix Proteins; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C073119:TAP1 protein, human; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D016753:Interleukin-10; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex