MHC class I-restricted responses mediated by CD8+ T lymphocytes are not frequently associated with protective immunity to bacterial pathogens. The murine response to Listeria monocytogenes, however, is an exception. Virulent Listeria can access the cytosol of epithelial cells, hepatocytes, macrophages, etc., and the proteins secreted into the host cell cytosol become substrates for MHC class I-restricted processing and presentation. Correlating with this intracellular niche, adoptive transfer and deletion experiments show that CD8+ T-cell immunity is more effective in clearing a Listeria infection than is CD4+ T-cell immunity. Recent work has demonstrated that avirulent forms of Listeria, such as heat-killed organisms, can also present peptide antigen to CD8+ cytotoxic T-cells via the specialized MHC class Ib molecule, H2-M3. H2-M3 can load hydrophobic peptides initiating with fMet derived from Listeria in macrophage phagocytic vacuoles for presentation at the cell surface. Previous work has demonstrated that H2-M3-restricted, CD8+ T-cells can also provide protection against Listeria. The goals of this application are to discover more about the types of bacterial proteins that provide epitopes for M3-restricted immunity. In this way, one may be able to predict which N-terminal peptides of pathogen-derived proteins are presented by this pathway. It is also the goal of the investigator to extend this form of immunity from a single bacterial pathogen which gets into the host cell cytosol, to the broader range of intracellular bacteria that remain enclosed in a host cell vacuole. The investigator aims to shed more light on how MHC class Ia- and class Ib-restricted bacterial antigens are presented to cytotoxic T-cell precursors to initiate a response in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019335-22
Application #
6510119
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Deckhut Augustine, Alison M
Project Start
1990-06-01
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
22
Fiscal Year
2002
Total Cost
$250,063
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bergsbaken, Tessa; Bevan, Michael J (2015) Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8? T cells responding to infection. Nat Immunol 16:406-14
Bergsbaken, Tessa; Bevan, Michael J (2015) Cutting Edge: Caspase-11 Limits the Response of CD8+ T Cells to Low-Abundance and Low-Affinity Antigens. J Immunol 195:41-5
Mehlhop-Williams, Erin R; Bevan, Michael J (2014) Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation. J Exp Med 211:345-56
Park, Heon; Tsang, Mark; Iritani, Brian M et al. (2014) Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proc Natl Acad Sci U S A 111:7066-71
Zhang, Nu; Bevan, Michael J (2013) Transforming growth factor-? signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39:687-96
Chu, Talyn; Tyznik, Aaron J; Roepke, Sarah et al. (2013) Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner. Cell Rep 3:701-8
Zhang, Nu; Bevan, Michael J (2012) TGF-? signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat Immunol 13:667-73
Prlic, Martin; Sacks, Jilian A; Bevan, Michael J (2012) Dissociating markers of senescence and protective ability in memory T cells. PLoS One 7:e32576
Zhang, Nu; Bevan, Michael J (2011) CD8(+) T cells: foot soldiers of the immune system. Immunity 35:161-8
Bevan, Michael J (2011) Understand memory, design better vaccines. Nat Immunol 12:463-5

Showing the most recent 10 out of 93 publications