title: Cholesterol lowering drug may influence cellular immune response by altering MHC II function.
abstract: Major histocompatibility complex class II (MHC II) expressed on the surface of antigen-presenting cells (APCs) displays peptides to CD4⁺ T cells. Depletion of membrane cholesterol from APCs by methyl β-cyclodextrin treatment compromises peptide-MHC II complex formation coupled with impaired binding of conformational antibody, which binds close to the peptide binding groove of MHC II. Interestingly, the total cell surface of MHC II remains unaltered. These defects can be corrected by restoring membrane cholesterol. In silico docking studies with a three-dimensional model showed the presence of a cholesterol binding site in the transmembrane domain of MHC II (TM-MHC-II). From the binding studies it was clear that cholesterol, indeed, interacts with the TM-MHC-II and alters its conformation. Mutation of cholesterol binding residues (F240, L243, and F246) in the TM-MHC-II decreased the affinity for cholesterol. Furthermore, transfection of CHO cells with full-length mutant MHC II, but not wild-type MHC II, failed to activate antigen-specific T cells coupled with decreased binding of conformation-specific antibodies. Thus, cholesterol-induced conformational change of TM-MHC-II may allosterically modulate the peptide binding groove of MHC II leading to T cell activation.
authors.affiliation: Infectious Diseases and Immunology and CSIR -Indian Institute of Chemical Biology, Jadavpur, Kolkata-700032, India.
authors.forename: Koushik
authors.initials: K
authors.lastname: Roy
authors.forename: Moumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Tuhin Kumar
authors.initials: TK
authors.lastname: Pal
authors.forename: Saikat
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000924:Anticholesteremic Agents; D000949:Histocompatibility Antigens Class II; D002784:Cholesterol
keywords: allostery; major histocompatibility complex class II; major histocompatibility complex class II conformation; peptide-major histocompatibility complex class II; statin and major histocompatibility complex class II
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