Pasare, C. & Medzhitov, R. Toll-like receptors: linking innate and adaptive immunity. Microbes Infect. 6, 1382-1387

Howard Hughes Medical Institute, Section of Immunobiology, 300 Cedar Street, TAC S660, Yale University School of Medicine, New Haven, CT 06510, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 02/2005; 560(15):11-8. DOI: 10.1007/0-387-24180-9_2
Source: PubMed

ABSTRACT Work in recent years has shown an essential role for Toll-like receptors (TLRs) in the activation of innate and adaptive immunity in vertebrate animals. These germ-line encoded receptors, expressed on a diverse variety of cells and tissues, recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. Ligand recognition induces a conserved host defense program, which includes production of inflammatory cytokines, upregulation of costimulatory molecules, and induction of antimicrobial defenses. Importantly, activation of dendritic cells by TLR ligands is necessary for their maturation and consequent ability to initiate adaptive immune responses. How responses are tailored by individual TLRs to contain specific classes of pathogens is not yet clear.

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    • "Dendritic cells (DC) are important antigenpresenting cells (APC) that participate in innate and acquired immunity (Pasare and Medzhitov 2005, Iwasaki and Medzhitov 2010). DC initiate immune responses that control and eliminate pathogens (Joffre et al. 2009). "
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    ABSTRACT: Dendritic cells (DC) are antigen-presenting cells (APC) that are important for innate and acquired immune responses. Owing to their involvement in autoinflammation, autoimmunity and cancer, DC are useful cellular models for biomedical research. Appropriate DC production in vitro could aid the study of DC in many human diseases. We used fluorochrome-based flow cytometry assays to analyze the effects of culture period and maturation of monocyte-derived DC (MoDC) on their viability and necrosis, purity, CD11c expression and phagocytic capacity. The morphological changes that occur as purified monocytes become DC were assessed at 24 and 72 h, and 6 and 9 days in culture. The dynamics of certain cell surface markers of monocytes and mature MoDC (mMoDC) also were assessed using fluorescence-based assays. We found that day 6 of culture yielded the most functional immature MoDC (iMoDC) with maximal viability, purity, CD11c expression and appropriate phagocytic capacity. Mass production of viable MoDC could be useful for immunotherapy.
    Biotechnic & Histochemistry 04/2015; 90(6):1-8. DOI:10.3109/10520295.2015.1017536 · 1.44 Impact Factor
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    • "+ CD8 + DP thymocytes (Supplement Fig. S2). Presence of TLR4 on the differentiated cells indicates these cells have the potential for directly sensing pathogen-associated molecule and would bridge innate signaling with adaptive immune response [25] [29] "
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    ABSTRACT: Nonconventional innate memory CD8(+) T cells characteristically expressing CD44, CD122, eomesodermin (Eomes) and promyelocytic leukemia zinc finger (PLZF) were derived in culture from CD4(+)CD8(+) double positive (DP) thymocytes of normal BALB/c and C57BL/6 mice. These culture-differentiated cells constitutively express toll-like receptor (TLR)4 and release interferon (IFN)-γ and interleukin (IL)-10. We show the TLR4-ligand lipopolysaccharide (LPS) stimulate the TLR and up-regulate IFN-γ skewing the cells towards type 1 polarization. In presence of LPS these cells also express suppressor of cytokine signaling (SOCS)1 and thus suppress IL-10 expression. In contrast, heat shock protein (Hsp)70 down-regulated TLR4 augmenting the anti-inflammatory cytokine IL-10. In association with IL-10 release IFN-γ was abrogated. The programmed cell death (PD)-1 mostly present in regulatory T cells was stimulated in these IL-10 producing cells by Hsp70 and not LPS indicating the cells can be driven to two contrast outcomes by the two TLR4 ligands. Our work provides a scope for in vitro monitoring of CD8(+) T cells to decipher important immune therapeutic option during infection or sepsis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine 02/2015; 73(1):44-52. DOI:10.1016/j.cyto.2015.01.018 · 2.66 Impact Factor
    • "Immature DC have high endocytic capacity, express various intra-and extracellular pathogen recognition receptors, such as toll-like receptors (TLR), and continuously sample their surroundings for danger signals. TLR-triggering results in phenotypical changes, facilitated Ag processing, MHC presentation and increased cytokine production, a process termed DC maturation [4]. Therapeutic vaccinations against cancer are centered on the delivery of tumor associated Ag (TAA) to DC which then initiate Agspecific T cell responses [5] [6]. "
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    ABSTRACT: Dendritic cells (DC) play a prominent role in the priming of CD8(+) T cells. Vaccination is a promising treatment to boost tumor-specific CD8(+) T cells which is crucially dependent on adequate delivery of the vaccine to DC. Upon subcutaneous (s.c.) injection, only a small fraction of the vaccine is delivered to DC whereas the majority is cleared by the body or engulfed by other immune cells. To overcome this, we studied vaccine delivery to DC via CD40-targeting using a multi-compound particulate vaccine with the aim to induce potent CD8(+) T cell responses. To this end, biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP) were formulated encapsulating a protein Ag, Pam3CSK4 and Poly(I:C) and coated with an agonistic αCD40-mAb (NP-CD40). Targeting NP to CD40 led to very efficient and selective delivery to DC in vivo upon s.c. injection and improved priming of CD8(+) T cells against two independent tumor associated Ag. Therapeutic application of NP-CD40 enhanced tumor control and prolonged survival of tumor-bearing mice. We conclude that CD40-mediated delivery to DC of NP-vaccines, co-encapsulating Ag and adjuvants, efficiently drives specific T cell responses, and therefore, is an attractive method to improve the efficacy of protein based cancer vaccines undergoing clinical testing in the clinic. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Biomaterials 11/2014; 40. DOI:10.1016/j.biomaterials.2014.10.053 · 8.56 Impact Factor
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