An acid protease secreted by transformed cells interferes with antigen processing

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Antigen processing is crucial for T-cell recognition and immune responses.
• Lysosomal cathepsin L, a key enzyme in antigen processing, is involved in breaking down proteins into peptides for presentation.
• The role of exogenous acid proteases in modulating antigen processing remains incompletely understood.

Purpose of the Study:

• To investigate the impact of exogenous acid proteases on antigen processing by antigen-presenting cells.
• To elucidate the mechanism by which major excreted protein (MEP) affects antigen presentation.
• To explore the potential contribution of acid proteases to impaired immunocompetence in tumor-bearing hosts.

Main Methods:

• Utilized Chinese hamster ovary (CHO) cells expressing major histocompatability complex class II molecules.
• Introduced exogenous major excreted protein (MEP) and pigeon cytochrome c into CHO cells.
• Assessed T-cell hybridoma 2B4 response to antigen presentation.
• Investigated the effect of mannose 6-phosphate on MEP internalization and function.

Main Results:

• MEP inhibited the antigen-specific T-cell response, indicating impaired antigen processing.
• MEP's protease activity is optimal under acidic conditions, consistent with lysosomal environments.
• Mannose 6-phosphate blocked MEP internalization, preventing its effect on antigen processing.
• Simultaneous entry of antigen and MEP was required for antigen destruction.
• A processed fragment of cytochrome c stimulated T-cell response in the presence of MEP.

Conclusions:

• Antigen processing necessitates internalization into an acidic cellular compartment.
• Exogenous acid proteases, such as MEP, can interfere with antigen processing.
• These findings provide a novel model to study the role of acid proteases in tumor-associated immunodeficiency.