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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 and Cornella-Taracido, Ivan and Galli-Stampino, Luisa and Jain, Rishi and Harrington, Edmund and Isome, Yuko and Tavarini, Simona and Sammicheli, Chiara and Nuti, Sandra and Mbow, Lamine and Valiante, Nicholas M. and Tallarico, John and 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

Abstract

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
URI: https://oak.novartis.com/id/eprint/4211

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