The P9 peptide sidechain specificity of I-Ad

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The murine MHC class II variant I-Ad influences susceptibility to herpes simplex virus (HSV)-induced keratitis and type 1 diabetes.
• The peptide-binding groove's P9 pocket is critical for determining T-cell responses and autoimmune disease associations.

Purpose of the Study:

• To analyze the peptide sidechain specificity of the I-Ad P9 pocket.
• To understand how P9 pocket interactions influence T-cell responses and autoimmune disease susceptibility.

Main Methods:

• Assessment of T-cell responses to modified peptides.
• Analysis of I-Ad binding capacity with position 446-substituted analogs of IgG2a heavy chain peptides.
• Comparison of I-Ad and I-Ag7 P9 pocket specificities.

Main Results:

• Engagement of the P9 pocket is crucial for peptide presentation, with sidechain size, not charge, determining binding.
• Small, uncharged sidechains are favored, while acidic, aromatic, lysine, and arginine residues are disfavored.
• I-Ad (Serine beta57) specificity differs from I-Ag7 (Aspartic acid beta57), impacting diabetes susceptibility.
• Susceptibility to HSV keratitis in IgG2a(a) mice is linked to inefficient thymic presentation of autologous IgG2a due to P9 pocket binding limitations.

Conclusions:

• Polymorphism at residue beta57 significantly affects autoimmune disease susceptibility through P9 pocket specificity.
• The P9 pocket's size-selectivity explains differential susceptibility to HSV keratitis and protection against type 1 diabetes conferred by IgG2a allotypes.