Three dimensional structure directs T-cell epitope dominance associated with allergy

Area of Science:

• Immunology
• Allergy Research
• Structural Biology

Background:

• CD4+ T-cell epitope immunodominance is not fully explained by peptide binding to MHC class II molecules.
• Previous studies suggest a correlation between immunodominance and conformational flexibility in antigens.

Purpose of the Study:

• To investigate the relationship between allergen epitope immunodominance and conformational flexibility.
• To understand the structural basis of T-cell responses to allergens.

Main Methods:

• Analysis of published T-cell responses to venom and aeroallergens.
• Construction of epitope dominance profiles.
• Correlation of epitope dominance with conformational flexibility metrics (B factors, solvent accessibility, COREX stability, sequence entropy).

Main Results:

• Allergenic epitopes were found to be preferentially located adjacent to, or excluded from, flexible segments within allergen structures.
• This finding challenges simple models of immunodominance based solely on peptide-MHC interactions.

Conclusions:

• The initiation of allergic responses involves preferential loading of N- and/or C-terminal ends of proteolytic processing intermediates into antigen-presenting proteins.
• This preferential loading primes CD4+ T cells, influencing the immune response to allergens.