Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis

Area of Science:

• Immunology
• Biochemistry

Background:

• T cells recognize processed protein fragments (peptides) presented by antigen-presenting cells.
• The precise mechanisms governing peptide selection and antigen immunogenicity remain incompletely understood.
• Predicting and manipulating antigen immunogenicity is challenging.

Purpose of the Study:

• To investigate the role of lysosomal proteolysis susceptibility in determining protein antigen immunogenicity in vivo.
• To compare the immunogenicity of proteins with identical sequences and structures but varying resistance to lysosomal degradation.

Main Methods:

• Immunization of mice with model antigens (RNase, horseradish peroxidase) adsorbed onto aluminum hydroxide adjuvant.
• Measurement of serum IgG responses as an indicator of antigen presentation on MHC class II molecules.
• Assessment of CD4+ T cell priming in vivo.

Main Results:

• Proteins with greater resistance to lysosomal proteolysis were significantly more immunogenic.
• Less digestible antigen forms induced more efficient T cell priming and robust antibody responses.
• Identical protein sequences and structures yielded different immunogenicities based on proteolysis resistance.

Conclusions:

• Antigen stability against lysosomal proteolysis is a critical factor in determining in vivo immunogenicity.
• This finding has significant implications for the rational design of vaccines.
• Manipulating antigen stability could enhance vaccine efficacy.