title: TLR agonists downregulate H2-O in CD8alpha- dendritic cells.
abstract: Peptide loading of MHC class II (MHCII) molecules is catalyzed by the nonclassical MHCII-related molecule H2-M. H2-O, another MHCII-like molecule, associates with H2-M and modulates H2-M function. The MHCII presentation pathway is tightly regulated in dendritic cells (DCs), yet how the key modulators of MHCII presentation, H2-M and H2-O, are affected in different DC subsets in response to maturation is unknown. In this study, we show that H2-O is markedly downregulated in vivo in mouse CD8α(-) DCs in response to a broad array of TLR agonists. In contrast, CD8α(+) DCs only modestly downregulated H2-O in response to TLR agonists. H2-M levels were slightly downmodulated in both CD8α(-) and CD8α(+) DCs. As a consequence, H2-M/H2-O ratios significantly increased for CD8α(-) but not for CD8α(+) DCs. The TLR-mediated downregulation was DC specific, as B cells did not show significant H2-O and H2-M downregulation. TLR4 signaling was required to mediate DC H2-O downregulation in response to LPS. Finally, our studies showed that the mechanism of H2-O downregulation was likely due to direct protein degradation of H2-O as well as downregulation of H2-O mRNA levels. The differential H2-O and H2-M modulation after DC maturation supports the proposed roles of CD8α(-) DCs in initiating CD4-restricted immune responses by optimal MHCII presentation and of CD8α(+) DCs in promoting immune tolerance via presentation of low levels of MHCII-peptide.
authors.affiliation: Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Porter
authors.forename: Woelsung
authors.initials: W
authors.lastname: Yi
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Denzin
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000819:agonists
chemical_list: D016827:CD8 Antigens; C431698:CD8alpha antigen; C416186:H-2O antigen; C416189:H2-M antigens; D000949:Histocompatibility Antigens Class II; D051193:Toll-Like Receptors