The long term goal of this project is to understand how the antigen processing mechanism generates antigenic peptide/MHC class I complexes by unconventional (cryptic) translation. Recent studies, from several different laboratories have demonstrated that naturally processed peptides presented by MHC class I molecules on the surface of tumors, virally infected cells, and transfected cells can arise from regions of messenger RNA that were not expected to be translated. The mechanism by which cells sample this cryptic source of antigenic peptides versus the conventional source representing by-products of protein turn-over is not known. In addition, to what extent these cryptic peptides contribute to the diverse pool of peptides presented by MHC molecules and their immunological role remains to be established. In this proposal we will test the hypotheses that these unconventional, cryptic peptides could be products of a novel translational mechanism and could play a significant immunological role in normal animals. Using unique reagents and methods established in this laboratory these hypotheses will be tested by, (1) defining the context rules which determine how cryptic translation of the mRNA occurs and results in expression of peptide/MHC class I complexes, (2) determining the immunological role of cryptic peptide/MHC class I complexes in normal transgenic mice, and, (3) analyzing the different steps in the pathway for generation of cryptic peptide/MHC class I complexes. It is expected that improved understanding of the mechanism for generation of cryptic peptide/MHC complexes will not only provide novel sources of antigenic peptides and approaches to vaccine design but will also yield new insights into protein translation and immunesurveillance mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044864-02
Application #
6349891
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Kraemer, Kristy A
Project Start
2000-02-15
Project End
2005-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$280,415
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Prasad, Sharanya; Starck, Shelley R; Shastri, Nilabh (2016) Presentation of Cryptic Peptides by MHC Class I Is Enhanced by Inflammatory Stimuli. J Immunol 197:2981-2991
Starck, Shelley R; Shastri, Nilabh (2016) Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance. Immunol Rev 272:8-16
Shastri, Nilabh; Nagarajan, Niranjana; Lind, Kristin C et al. (2014) Monitoring peptide processing for MHC class I molecules in the endoplasmic reticulum. Curr Opin Immunol 26:123-7
Nagarajan, Niranjana A; Shastri, Nilabh (2013) Immune surveillance for ERAAP dysfunction. Mol Immunol 55:120-2
Nagarajan, Niranjana A; Gonzalez, Federico; Shastri, Nilabh (2012) Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. Nat Immunol 13:579-86
Blanchard, Nicolas; Shastri, Nilabh (2010) Topological journey of parasite-derived antigens for presentation by MHC class I molecules. Trends Immunol 31:414-21
Blanchard, Nicolas; Shastri, Nilabh (2008) Coping with loss of perfection in the MHC class I peptide repertoire. Curr Opin Immunol 20:82-8
Schwab, Susan R; Shugart, Jessica A; Horng, Tiffany et al. (2004) Unanticipated antigens: translation initiation at CUG with leucine. PLoS Biol 2:e366