Multiple antigen-specific processing pathways for activating naive CD8+ T cells in vivo

Area of Science:

• Immunology
• Molecular Biology
• Vaccine Development

Background:

• Current understanding of viral antigen processing for MHC class I presentation relies heavily on in vitro studies using nonprofessional antigen-presenting cells (pAPCs).
• This in vitro approach is limited as it doesn't fully replicate in vivo immune responses where pAPCs activate naive CD8(+) T cells.

Purpose of the Study:

• To investigate the in vivo antigen processing and presentation by pAPCs, focusing on the role of the Transporter Associated with Protein Processing (TAP).
• To understand how antigen presentation pathways in vivo differ from in vitro findings, particularly for vaccine design.

Main Methods:

• Utilized TAP1-deficient (TAP1(-/-)) mice to assess the immunogenicity of model antigens synthesized by recombinant vaccinia viruses.
• Compared in vitro and in vivo antigen presentation efficiencies, including TAP-dependent and independent pathways.

Main Results:

• Demonstrated a correlation between TAP-independent antigen presentation in vitro and naive T cell activation in vivo.
• Provided the first in vivo evidence for proteolytic processing of antigenic peptides within the secretory pathway.
• Observed TAP-independent in vivo presentation of a specific peptide (SIINFEKL) from ovalbumin (OVA), contrasting with its strict TAP dependence in vitro.
• Showed that the same peptide presented within a fusion protein remained TAP-dependent in vivo.

Conclusions:

• Established the existence of determinant-specific processing pathways crucial for generating antiviral T cell responses in vivo.
• Identified potential protein-specific differences in antigen presentation, with cross-priming suggested as a likely underlying mechanism.