title: Endocytic pH regulates cell surface localization of glycolipid antigen loaded CD1d complexes.
abstract: Invariant natural killer T (iNKT) cells recognize glycolipid antigens presented by CD1d, an antigen presenting protein structurally similar to MHC class I. Stimulation of iNKT cells by glycolipid antigens can induce strong immune responses in vivo, with rapid production of a wide variety of cytokines including those classically associated with either T helper type 1 (Th1) or type 2 (Th2) responses. Alterations in the lipid tails or other portions of CD1d-presented glycolipid ligands can bias the iNKT response towards production of predominantly Th1 or Th2 associated cytokines. However, the mechanism accounting for this structure-activity relationship remains controversial. The Th1-biasing glycolipids have been found to consistently form complexes with CD1d that preferentially localize to plasma membrane cholesterol rich microdomains (lipid rafts), whereas CD1d complexes formed with Th2-biasing ligands are excluded from these microdomains. Here we show that neutralization of endosomal pH enhanced localization of CD1d complexes containing Th2-biasing glycolipids to plasma membrane lipid rafts of antigen presenting cells (APC). Transfer of APCs presenting these "stabilized" CD1d/αGC complexes into mice resulted in immune responses with a more prominent Th1-like bias, characterized by increased NK cell transactivation and interferon-γ production. These findings support a model in which low endosomal pH controls stability and lipid raft localization of CD1d-glycolipid complexes to regulate the outcome of iNKT cell mediated responses.
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Pooja
authors: P
authors: Arora
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Shalu S
authors: SS
authors: Kharkwal
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Tony W
authors: TW
authors: Ng
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Shajo
authors: S
authors: Kunnath-Velayudhan
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Neeraj K
authors: NK
authors: Saini
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Christopher T
authors: CT
authors: Johndrow
authors: Department of Chemistry and NUS Medchem Program of The Life Sciences Institute, National University of Singapore 117543, Singapore.
authors: Young-Tae
authors: YT
authors: Chang
authors: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Gurdyal S
authors: GS
authors: Besra
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: steven.porcelli@einstein.yu.edu.
authors: Steven A
authors: SA
authors: Porcelli
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006017:Glycolipids / Q000737:chemistry / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D006017:Glycolipids
keywords: Antigen presentation; CD1d; Dendritic cells; Endosomal pH; Endosomal presentation; Glycolipid; IFNγ secretion; NK activation; NKT cells; pH neutralization; transactivation; αGC