Protein Trafficking and Unchaperoned Translation During a Viral Infection Determine Antigen Processing Outcomes for MHC Class I Direct Presentation
The protection against viral infections and cancers afforded by CD8+ T cells, relies on effective antigen processing and presentation. The primary source of parent antigens that are rapidly and efficiently converted into peptides, appears to be the pool of nascent proteins. However, the factors that drive this conversion are not entirely understood. In this body of work, we sought to understand the impact of multiple processing pathways for ER-targeted glycoproteins on the CD8+ T cell repertoire. Just like their cytosolic counterparts, mislocalized proteins requiring ER based translation can access the ubiquitin-proteasome system directly. In addition, glycoproteins that have failed quality control can be redirected from the ER back to the cytosol via ER associated degradation. We found that peptides arising from mislocalized glycoproteins play a far more significant part in driving optimal CD8+ T cell numbers and functionality compared to ERAD processed epitopes. We also sought to understand the factors that enhance antigen presentation during a viral infection. Our data suggest that translational stress imposed by an infection can lead to ribosomes lacking the chaperones which would normally prevent aggregation and aid in the folding and quality control of nascent proteins. Taken together, our findings expand the knowledge of the basic mechanisms underscoring antigen processing and presentation and may lead to applications such as rational CD8+ T cell vaccine design against viral infections and cancers.
Cosma, Gabriela Ligia, "Protein Trafficking and Unchaperoned Translation During a Viral Infection Determine Antigen Processing Outcomes for MHC Class I Direct Presentation" (2022). ETD Collection for Thomas Jefferson University. AAI29068283.