MHC class I molecules present peptide to CD8+ cytolytic T lymphocytes with brilliant specificity, thus ensuring accurate identification of virus-infected and tumor cells. However, several of the functions of class I molecules are limited by peptide and/or beta2m dissociation from the heavy chain. Indeed blocking class I heavy chain assembly with peptide and/or beta2m are major pathways used by tumors and viruses to evade detection by CD8+ T cells. To circumvent limitation of class I as a consequence of their propensity to disassemble, we have engineered class I molecules as single chain trimers (SCTs) with the composition of peptide--spacer--beta2m--spacer--heavy chain. Our recently published findings have shown that SCT have remarkable properties including extraordinary stability at the cell surface and potent stimulation of class I/peptide-specific T cells and antibodies. In this grant we will define the mechanisms by which SCT are potent immune stimulators and test their unique advantages over native class I molecules in DC based immunotherapies and when used as DNA vaccines against tumors or viruses. Of particular significance, these findings will determine whether SCT present antigen following DNA vaccination by cross priming or direct presentation to CD8+ T cells. Furthermore we will test whether the keen ability of SCT to expand CD8+ T cells ex vivo results from impaired interactions with inhibitory receptors and/or less dependency on costimulation. In addition we will exploit the unique ability of SCT to elicit MHC-restricted antibodies to raise mAbs to disease-relevant class I/peptide complexes. Such mAb will be invaluable for quantifying expression of specific class I/peptide complexes during disease progression and determine how this correlates with the activation and effector function of CD8+ T cells against viruses and tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055849-02
Application #
6857064
Study Section
Immunobiology Study Section (IMB)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$344,250
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Hoerter, John A H; Brzostek, Joanna; Artyomov, Maxim N et al. (2013) Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC. J Exp Med 210:1807-21
McCoy 4th, William H; Wang, Xiaoli; Yokoyama, Wayne M et al. (2013) Cowpox virus employs a two-pronged strategy to outflank MHCI antigen presentation. Mol Immunol 55:156-8
Li, Lijin; Kim, Sojung; Herndon, John M et al. (2012) Cross-dressed CD8?+/CD103+ dendritic cells prime CD8+ T cells following vaccination. Proc Natl Acad Sci U S A 109:12716-21
Carreno, Beatriz M; Becker-Hapak, Michelle; Chan, Megan et al. (2012) Amino-terminal extended peptide single-chain trimers are potent synthetic agonists for memory human CD8+ T cells. J Immunol 188:5839-49
Kim, Sojung; Zuiani, Adam; Carrero, Javier A et al. (2012) Single chain MHC I trimer-based DNA vaccines for protection against Listeria monocytogenes infection. Vaccine 30:2178-86
Kim, Sojung; Li, Lijin; McMurtrey, Curtis P et al. (2010) Single-chain HLA-A2 MHC trimers that incorporate an immundominant peptide elicit protective T cell immunity against lethal West Nile virus infection. J Immunol 184:4423-30
Hansen, Ted H; Connolly, Janet M; Gould, Keith G et al. (2010) Basic and translational applications of engineered MHC class I proteins. Trends Immunol 31:363-9
Li, Lijin; Herndon, John M; Truscott, Steven M et al. (2010) Engineering superior DNA vaccines: MHC class I single chain trimers bypass antigen processing and enhance the immune response to low affinity antigens. Vaccine 28:1911-8
Hansen, Ted; Yu, Y Y Lawrence; Fremont, Daved H (2009) Preparation of stable single-chain trimers engineered with peptide, beta2 microglobulin, and MHC heavy chain. Curr Protoc Immunol Chapter 17:Unit17.5

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