Download 2016 department of medicine research day

2016 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Presentation: Human Vaults: A Huge Tiny Mystery and Novel Cellular Immune
Vaccine Vector
Speaker: Otto O. Yang MD
Division: Infectious Diseases
PLENARY SESSION ABSTRACT
CD8+ cytotoxic T lymphocytes (CTLs) have emerged as a critical arm of immunity to clear cells with
abnormal protein antigens, namely virus-infected and malignant cells. Eliciting CTL responses with
vaccines has been highly problematic, because this requires protein delivery to the cytoplasmic
compartment and MHC class I pathway, whereas protein or killed pathogen vaccines are taken up into
the MHC class II pathway. Attempts to generate vaccines for CTL responses generally have utilized
recombinant viral vectors. We find that the human “vault” can serve as a remarkably efficient nonviral vector to generate MHC class I dependent CTL responses against antigens.
“Vaults” are endogenous nano-sized protein structures found plentifully in all nucleated human cells,
and highly conserved across the animal kingdom except for insects. Despite their discovery here at
UCLA 30 years ago by Dr. Rome, their function remains obscure. His group has developed methods to
produce recombinant vaults that are ~70 by ~40 nanometer shell structures composed of 78 copies of
a single protein, the Major Vault Protein (MVP), and to package proteins into these structures. In
collaboration, we have demonstrated that recombinant human vaults can deliver antigens with
remarkable efficiency via the MHC class I pathway in human cells in vitro and mice in vivo. In mice,
CTL responses against an HIV-1 protein fragment reach frequencies of over 50%, compared to ~1%
for the only CTL-based vaccines to reach efficacy trials in humans. These are T-helper type 1
responses that are critical for clearing virus-infected and malignant cells. Moreover, vaults can be
delivered intranasally and generate vigorous mucosal immunity. The mechanism for this
unprecedented capability to generate CTL responses is unclear, but preliminary experiments suggest
that antigen-presenting cells may possess specific receptor(s) for vault uptake.
Thus recombinant human vaults offer a promising pathway as vaccine vectors to generate CTL
responses for prevent or therapy of viral infections and potentially malignancies.