Mobilizing TAP-independent CD8 T cells through non-canonical cross-presentation

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.

Grant Number: 5R01AI170897-04
NIH Institute/Center: NIH
Principal Investigator: Julie Magarian Blander