Reshaping the Bet v 1 fold modulates T(H) polarization

Area of Science:

• Immunology
• Allergen structure-function relationships
• Protein engineering

Background:

• Proteins can trigger T(H)2-biased and IgE-mediated immune responses through various mechanisms.
• The major birch pollen allergen, Bet v 1, is known to induce T(H)2 polarization, potentially via a fold-dependent mechanism.

Purpose of the Study:

• To investigate the role of protein structure in the T(H)2-polarizing activity of Bet v 1.
• To create and analyze a Bet v 1 derivative with an altered fold.

Main Methods:

• Computer-aided analysis identified a mutation-susceptible region in Bet v 1.
• A Bet v 1 derivative (BM4) was created by replacing 7 amino acids with homologous Mal d 1 sequences.
• Immunological assays were performed using human peripheral blood mononuclear cells (PBMCs) and a mouse model.

Main Results:

• The BM4 derivative exhibited a loss of the Bet v 1-like fold and altered immunologic properties.
• BM4 induced increased T-cell proliferation in human PBMCs and a mixed T(H)1/T(H)2 response in mice, unlike wild-type Bet v 1.
• BM4 showed enhanced uptake by dendritic cells and reduced susceptibility to proteolysis.

Conclusions:

• Modifying the 3D structure of Bet v 1 significantly alters its immunologic properties.
• Fold alteration impacts dendritic cell interactions and shifts immune polarization towards a mixed T(H)1/T(H)2 response.
• These findings highlight the importance of protein structure in allergenicity and immune response modulation.