title: MHC class II presentation is controlled by the lysosomal small GTPase, Arl8b.
abstract: Dendritic cells (DCs) are specialized APCs with the ability to prime naive T cells. DCs first sample Ags from the environment and then orchestrate their processing and loading onto MHC class II (MHC II) Ag-presenting molecules in lysosomes. Once MHC II molecules have bound a peptide, the MHC II-peptide complex is delivered to the cell surface for presentation to CD4(+) T cells. Regulation of Ag uptake via macropinocytosis and phagocytosis has been extensively studied, as well as trafficking in early endocytic vesicles notably regulated by the small GTPase Rab5 and its effectors. However, little is known about the regulators of Ag delivery from early endosomes to lysosomal compartments where the proper pH, proteases, MHC II, invariant chain, and HLA-DM reside, awaiting exogenous Ags for loading. In this article, we report the crucial role of the small GTPase ADP-ribosylation factor-like 8b (Arl8b) in MHC II presentation in DCs. We show for the first time, to our knowledge, that Arl8b localizes to MHC II compartments in DCs and regulates formation of MHC II-peptide complexes. Arl8b-silenced DCs display a defect in MHC II-Ag complex formation and its delivery to the cell surface during infection resulting in a defect in T cell recognition. Our results highlight the role of Arl8b as a trafficking regulator of the late stage of complex formation and MHC II presentation in DCs.
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Xavier
authors: X
authors: Michelet
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Salil
authors: S
authors: Garg
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors: Benjamin J
authors: BJ
authors: Wolf
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Division of Cell Biology and Immunology, Institute of Microbial Technology, Chandigarh 160036, India; and.
authors: Amit
authors: A
authors: Tuli
authors: Singapore Immunology Network, Agency for Science, Technology and Research, 138648 Singapore.
authors: Paola
authors: P
authors: Ricciardi-Castagnoli
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; mbrenner@research.bwh.harvard.edu.
authors: Michael B
authors: MB
authors: Brenner
mesh_terms: D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D002645:Chickens; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D011992:Endosomes / Q000276:immunology; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D061251:Primary Cell Culture; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D000941:Antigens; C581820:Arl8B protein, mouse; D000949:Histocompatibility Antigens Class II; D034741:RNA, Small Interfering; D010047:Ovalbumin; D020727:ADP-Ribosylation Factors