Cross-Priming Mechanisms Induced by Microbial Products

University Of California San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): 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.