Modulation of T cell response to hGAD65 peptide epitopes

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• Human CD4 T cell responses are crucial for adaptive immunity.
• Glutamic acid decarboxylase (GAD) is an autoantigen implicated in autoimmune diseases.
• Altered peptide ligands (APLs) can modulate T cell responses.

Purpose of the Study:

• To investigate how modifications in APLs and HLA-DR4 molecules affect T cell responses to a hGAD65 epitope.
• To explore the impact of APL modifications at specific peptide-MHC binding pockets (p1 and p9) on T cell signaling avidity.
• To elucidate the structural basis for differential APL function.

Main Methods:

• Utilized human CD4 T cells and an epitope from human glutamic acid decarboxylase (hGAD65).
• Employed altered peptide ligands (APLs) with modifications at T cell receptor (TCR) contact residues.
• Tested various HLA-DR4 molecules with polymorphisms in peptide binding pockets (p1 and p9).
• Performed molecular homology modeling to analyze MHC-peptide interactions.

Main Results:

• Enhancing the p1 interaction (peptide or MHC modification) increased the antagonist activity of the APL.
• Modifications at the p9 pocket reversed APL function, leading to agonist activity.
• APL modifications differentially impacted TCR signaling efficiency and avidity.
• Structural modeling provided insights into the functional dichotomy observed.

Conclusions:

• The location of modifications in APLs and HLA-DR4 molecules critically determines their functional outcome (agonist vs. antagonist).
• Modifications influencing p1 interactions enhance APL antagonist properties.
• Modifications at p9 can convert APLs into agonists.
• Topographically distinct variations in MHC-peptide interactions lead to unique effects on TCR signaling, offering potential therapeutic strategies.