Kinetically distinct processing pathways diversify the CD8⁺ T cell response to a single viral epitope

Area of Science:

• Immunology
• Cell Biology
• Protein Trafficking

Background:

• The origins of peptides that activate CD8+ T cells are not fully understood.
• Glycoproteins present unique challenges due to complex intracellular trafficking pathways.

Purpose of the Study:

• To investigate the source of CD8+ T cell-activating peptides derived from glycoproteins.
• To determine how different protein trafficking routes impact T cell responses.

Main Methods:

• Engineered a glycoprotein-derived epitope with an N-linked glycosylation site.
• Analyzed peptide generation kinetics from distinct cellular fractions (cytosolic vs. translocated).
• Assessed CD8+ T cell expansion and function in response to peptides from different pathways.

Main Results:

• Rapid peptide production from a minor fraction of mislocalized cytosolic glycoproteins optimally stimulated CD8+ T cells.
• Delayed peptide generation from the major translocated glycoprotein fraction resulted in suboptimal T cell responses.
• Demonstrated a dual system of peptide generation influencing T cell response kinetics and antigenicity.

Conclusions:

• Protein mislocalization to the cytosol is a critical pathway for generating potent CD8+ T cell activators.
• Differential peptide processing kinetics from glycoprotein trafficking routes significantly modulate adaptive immune responses.
• Understanding these pathways is key to developing effective immunotherapies.