Wednesday, February 5, 2025
2/5/2025
PROPOSAL SUMMARY Major histocompatibility complex class I (MHC-I) molecules present peptides at the cell surface to CD8 T cells. The transporter associated with antigen processing (TAP) is a heterodimeric molecule of TAP1 and TAP2 that lies at the center of a macromolecular peptide loading complex tasked with loading and folding MHC-I molecules with peptides. TAP shuttles cytosolic proteasome-generated peptides across the membrane of the endoplasmic reticulum (ER) for luminal delivery and loading of MHC-I molecules. Given the crucial role of TAP in translocating peptides to MHC-I molecules, many clinically important human viruses such as Herpesviridae and Poxviridae have evolved strategies to block TAP and evade host CD8 T cell recognition. TAP blockade upon infection of dendritic cells (DC), which are responsible for naïve CD8 T cell priming, impairs conventional TAP-proteasome processing for the classic MHC-I presentation of peptides to CD8 T cells. In fact, the current paradigm holds that TAP blockade in DC renders these cells non-functional and incapable of priming a CD8 T cell response. Priming virus-specific CD8 T cells falls on uninfected TAP-sufficient bystander DC through cross-presentation, a process that enables MHC-I loading with viral peptides derived from DC internalized virus-infected dying cells. However, CD8 T cells primed by TAP-sufficient DC recognize dominant TAP-dependent peptides, whose presentation is severely reduced on tissues infected with immune evasive viruses. TAP-dependent CD8 T cells would also be mismatched to the TAP-independent peptides liberated by alternative TAP-independent processing of viral antigens and presented by MHC-I on those infected tissues. Either scenario creates a diminished or mismatched CD8 T cell target. How does the immune system get around this problem? We found that DC without functional TAP rely on cell-autonomous delivery of MHC-I from a new location, the ER-Golgi intermediate compartment (ERGIC), to internalized antigens to rescue MHC-I presentation and nevertheless cross-prime CD8 T cells. We call this pathway non-canonical cross-presentation. Our findings point to non-canonical cross-presentation as a previously unrecognized pathway for priming CD8 T cells that recognize TAP-independent epitopes and would be best-matched against immune evasive viruses. Studying non-canonical cross-presentation is important to understand the full spectrum of CD8 T cells that can be mobilized against infection, especially if such T cells provide potent local cross-protection within infected tissues. We seek to understand the role of non-canonical cross-presentation in priming a TAP-independent CD8 T cell response against viral infection. Using novel models, we will identify DC that conduct non-canonical cross-presentation, and define the repertoire of TAP-independent epitopes they present to antigen-specific TAP-independent CD8 T cells. We will create novel tools to track TAP- independent CD8 T cell responses and determine whether non-canonical cross-presentation can drive cross- protective immunity against viral variants and immune evasive viruses. Understanding non-canonical cross- presentation will inform universal vaccine design and new therapies for chronic and persistent viral infections.
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