Enhancement of dendritic cell antigen cross-presentation by CpG DNA involves type I IFN and stabilization of class I MHC mRNA.
Dendritic cells (DCs) internalize exogenous Ags and process them for cross-presentation by class I MHC (MHC-I) to CD8+ T cells. This processing can occur by transporter for Ag presentation (TAP)-dependent or TAP-independent mechanisms. We observed that CpG DNA enhanced cross-presentation of Ags by Flt-3L-cultured bone marrow-derived murine DCs by a type I IFN (IFN-alphabeta)-dependent mechanism. Myeloid DCs provided cross-presentation function in this system. Both TAP1 knockout and wild-type DCs showed enhanced cross-presentation when treated with CpG DNA at 26 degrees C, demonstrating that TAP is not essential to this regulatory mechanism, although TAP is an important determinant of MHC-I expression. Enhancement of cross-processing by CpG DNA did not involve increased Ag uptake or proteolysis but did correlate with IFN-alphabeta-dependent increases in expression of MHC-I mRNA and protein. Increased MHC-I mRNA levels resulted in part from stabilization of MHC-I mRNA, a novel posttranscriptional mechanism for regulation of MHC-I expression. Thus, a major mechanism by which CpG oligodeoxynucleotide increase cross presentation by DCs appears to be an IFN-alphabeta-mediated increase in MHC-I synthesis.
Kuchtey
John
J
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Chefalo
Peter J
PJ
Gray
Reginald C
RC
Ramachandra
Lakshmi
L
Harding
Clifford V
CV
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D045142:Cross-Priming / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000096:biosynthesis / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; C486171:Tap1 protein, mouse; D016899:Interferon-beta; D010047:Ovalbumin