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Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells

Russo, Carla, Cornella-Taracido, Ivan, Galli-Stampino, Luisa, Jain, Rishi, Harrington, Edmund, Isome, Yuko, Tavarini, Simona, Sammicheli, Chiara, Nuti, Sandra, Mbow, Lamine, Valiante, Nicholas M., Tallarico, John, De Gregorio, Ennio and Soldaini, Elisabetta (2011) Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells. Blood Journal, 117 (21). pp. 5683-5691. ISSN 0006-4971


Toll-like receptors (TLRs) 7 and 8 are intracellular sensors activated by single stranded RNA species generated during viral infections. Various synthetic small molecules can also activate TLR7 and/or 8; however the molecular mechanisms governing their TLR7/8 triggering remain largely unknown. To shed light on how small molecule agonists target TLRs, we labeled two imidazoquinolines, resiquimod and imiquimod, and one purine-like compound, SM360320, with two different fluorophores (TAMRA and AlexaFluor488) and monitored their intracellular localization in human plasmacytoid dendritic cells (pDCs). All fluorescent compounds induced the production of IFN TNF and IL-6 and the up-regulation of CD80 and CD86 by pDCs showing they retained TLR7 stimulating activity. Confocal imaging demonstrated that all compounds concentrated in LAMP1+CD63+HLA-DR+ endosomes, which represent the MHC class II loading compartment of pDCs. Moreover, CpG-B, which triggers TLR9 signaling from this endolysosomal compartment, co-localized with all 3 TLR7/8 small molecule agonists. By contrast, treatment of pDCs with bafilomycin A, an antagonist of the vacuolar-type proton ATPase that inhibits TLR7 and TLR9 signaling, prevented the accumulation of imiquimod-TAMRA, but not of CpG-B-TAMRA, in LAMP1+HLA-DR+ endosomes. These results indicate that a pH-driven concentration of small molecule TLR7 agonists in the MHC class II loading compartment is required for pDCs activation.

Item Type: Article
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Additional Information: The senior authors of this publication are from NV+D. This work is the result of a collaboration between NV+D, GNF, and NIBR. It covers the work of the "SMIP" team - small molecule immune potentiators - the NIBR contribution on this is primarily around providing tools for the subsequent biological studies. The manuscript is primarily authored by NV+D scientists.
Keywords: Immunobiology
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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