Antigen presentation by MHC class I molecules to CD8 T cells is a major pathway by which the acquired immune system detects and eliminates virus infected cells. All nucleated cells express MHC class I molecules and are thus potentially capable of direct antigen presentation to CD8 T cells upon infection. However, several, but not all, recent studies suggest that predominantly DCs (or a specific subset of DCs) are uniquely required for in vivo priming of CD8 T cells to virus. Because pathogens may not directly infect these requisite DCs, cross presentation pathways have been proposed;in essence, the infected cell may not be the primary antigen presenting cell. Additionally, for many arthropod-transmitted viruses, virus-specific antigens may require transfer from migratory DCs in the skin to lymph node resident DCs to efficiently prime CD8 T cells. However, the mechanism by which pathogen-specific antigens are shuttled from the infected cells to DCs or between DC subsets is unknown. Not surprisingly, these same issues of direct presentation vs. cross-presentation also apply to CD8 T cell responses to tumors or following DNA vaccination. As a novel strategy to elicit pathogen immunity, we have engineered preprocessed and preloaded MHC class I molecules as single chains of peptide, beta-2 microglobulin and class I heavy chain. We have termed these complexes single chain trimers or SCTs. SCTs are very stably expressed at the cell surface and we and others have demonstrated that SCTs elicit a robust CD8 T cell response. In this grant we will test whether SCTs confer protective immunity against viruses and bacteria, and probe the cellular and molecular basis of vivo priming of CD8 T cells following SCT vaccination. Our hypothesis is that SCT vaccine efficacy results from crosspresentation by CD81 DCs using a novel mechanism involving intercellular membrane exchange.

Public Health Relevance

Protective immunity to several pathogens requires that MHCI molecules bind antigenic peptides for presentation to CD8 T cells. However, to bind MHCI molecules, pathogen-derived peptides must compete with an extensive pool of endogenous peptides of the host. We have engineered MHCI molecules so that they can be pre-loaded with pathogen-derived peptides. In this grant, we will test the efficacy and mechanism of using these pre-loaded MHCI as vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055849-08
Application #
8213490
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2004-03-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
8
Fiscal Year
2012
Total Cost
$376,200
Indirect Cost
$128,700
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
King, Ben C; Hamblin, Angela D; Savage, Philip M et al. (2013) Antibody-peptide-MHC fusion conjugates target non-cognate T cells to kill tumour cells. Cancer Immunol Immunother 62:1093-105
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
Li, Lijin; Kim, Sojung; Herndon, John M et al. (2012) Cross-dressed CD8α+/CD103+ dendritic cells prime CD8+ T cells following vaccination. Proc Natl Acad Sci U S A 109:12716-21
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
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; 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
Wang, Baomei; Primeau, Tina M; Myers, Nancy et al. (2009) A single peptide-MHC complex positively selects a diverse and specific CD8 T cell repertoire. Science 326:871-4

Showing the most recent 10 out of 12 publications