As sentinels of the immune system, dendritic cells use pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), to recognize pathogen-associated molecular patterns (PAMPs). PAMP recognition provides a danger signal that activates and matures dendritic cells, leading to secretion of inflammatory cytokines and increased surface expression of molecules involved in antigen presentation and costimulation, optimizing the dendritic cell for CD4+ and CD8+ T cell stimulation. Dendritic cells are among the cells that can """"""""cross-present"""""""" exogenous antigen on MHC class I in order to """"""""cross-prime"""""""" CD8+ cytotoxic T lymphocytes (CTLs) against the exogenous antigen. Certain TLR agonists, such as poly(l:C) and immunostimulatory DNA sequences (ISS) containing unmethylated CpG dinucleotide motifs derived from bacterial DNA, are able to induce cross-priming of CD8+ T cells by dendritic cells. However, other TLR agonists, such as LPS, flagellin, and peptidoglycan do not induce cross-priming. We hypothesize that different TLR agonists differ in their abilities to induce cross-priming due to activation of differential signaling pathways that lead to variable induction of antigen processing events, surface molecule expression, and cytokine secretion needed for cross-priming. We propose to study the differential cross-priming abilities of TLR agonists in order to further characterize the poorly understood mechanisms of cross-priming and identify TLR signaling components important for cross-priming. Specifically, this will involve 1) characterizing the antigen processing pathways involved, 2) exploring the signaling mechanisms involved in TLR-induced cross-priming of CTLs, and 3) examining secreted cellular factors, including cytokines and heat shock proteins, involved in cross-priming. This work will provide insight into the link between microbial recognition and induction of cross-priming, elucidating mechanisms regulating CD8+ T cell activation that have wide-ranging implications from taming autoimmunity to creating CTL-eliciting vaccines effective against scourges such as HIV and tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI052406-02
Application #
6739092
Study Section
Allergy & Clinical Immunology-1 (AITC)
Program Officer
Prograis, Lawrence J
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$115,290
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Datta, Sandip K; Okamoto, Sharon; Hayashi, Tomoko et al. (2006) Vaccination with irradiated Listeria induces protective T cell immunity. Immunity 25:143-52
Datta, Sandip K; Raz, Eyal (2005) Induction of antigen cross-presentation by Toll-like receptors. Springer Semin Immunopathol 26:247-55
Datta, Sandip K; Cho, Hearn J; Takabayashi, Kenji et al. (2004) Antigen-immunostimulatory oligonucleotide conjugates: mechanisms and applications. Immunol Rev 199:217-26
Redecke, Vanessa; Hacker, Hans; Datta, Sandip K et al. (2004) Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 172:2739-43
Datta, Sandip K; Takabayashi, Kenji; Raz, Eyal (2003) The therapeutic potential of antigen-oligonucleotide conjugates. Ann N Y Acad Sci 1002:105-11