Cholesterol lowering drug may influence cellular immune response by altering MHC II function

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Major histocompatibility complex class II (MHC II) presents peptides to CD4+ T cells on antigen-presenting cells (APCs).
• Membrane cholesterol's role in MHC II function is not fully understood.

Purpose of the Study:

• To investigate the role of cholesterol in MHC II function and T cell activation.
• To identify the mechanism by which cholesterol affects MHC II.

Main Methods:

• Methyl β-cyclodextrin treatment to deplete cholesterol from APCs.
• In silico docking studies using a 3D model of MHC II.
• Cholesterol binding assays and site-directed mutagenesis.
• T cell activation assays in transfected cells.

Main Results:

• Cholesterol depletion impaired peptide-MHC II complex formation and conformational antibody binding.
• In silico studies identified a cholesterol binding site in the transmembrane domain of MHC II (TM-MHC-II).
• Cholesterol directly interacts with TM-MHC-II, altering its conformation.
• Mutating cholesterol binding residues reduced cholesterol affinity and abrogated T cell activation.
• Mutant MHC II failed to activate antigen-specific T cells and showed reduced antibody binding.

Conclusions:

• Cholesterol binding to TM-MHC-II induces a conformational change.
• This allosteric modulation of the peptide binding groove is crucial for T cell activation.
• Cholesterol is a key regulator of MHC II function and immune response.