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Immune Response and Danger Signals

Bénédicte Manoury
Team description

The aim of our work is to investigate how intracellular TLR trafficking and signalling are regulated at the steady state and during inflammation in dendritic cells.

Toll-like receptors (TLRs) recognize microbial products and play an essential role in innate and adaptive immunity. TLRs are divided in two families: membrane TLRs which sense the presence of proteins and lipids from bacteria and intracellular TLRs (TLR3, 7 and 9) localized in endosomes which, engage single stranded, double stranded RNA and methylated CpG DNA respectively from pathogens. In the absence of stimulation, intracellular TLRs are retained in the endoplasmic reticulum (ER) together with another ER resident protein, UNC93B1. Following nucleic acids sensing, intracellular TLRs traffic to endosomes where they require proteolytic cleavage to be functional and recruit the adaptor proteins MyD88 and TRIF. Their signalling which, leads to the production of pro-inflammatory cytokines and cell surface expression of co-stimulatory molecules, is essential to induce adaptive immunity in dendritic cells. The molecular chaperone UNC93B1 is essential for TLRs folding and trafficking and also set their activation threshold. Indeed, excessive TLR7 or TLR9 signalling can lead to autoimmunity and death. Thus, characterizing new factors involved in TLRs signalling is crucial in determining what influences the outcome of the immune response.

Our main objectives are:

  1. To identify new partners of interaction for UNC93B1 and to investigate the molecular mechanisms by which UNC93B1 shapes their function.
  2. To evaluate the actions of TLR9 in microglia versus peripheral immune cells during development of AD using specific models of mice lacking TLR9 and in human AD pathology.
  3. To investigate the role of TLR9 in immune tolerance and response to cancer.
Key publications
de Juan A, Tabtim-On D, Coillard A, Becher B, Goudot C, Segura E. The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters. Sci Signal. 2024; Oct 15;17(858):eadn6324. doi: 10.1126/scisignal.adn6324. PMID: 39405377 .
de Lavergne M, Maisonneuve L, Podsypanina K, Manoury B. The role of the antigen processing machinery in the regulation and trafficking of intracellular -Toll-like receptor molecules. Curr Opin Immunol. 2023; Oct;84:102375. Epub 2023 Aug 8. doi: 10.1016/j.coi.2023.102375. PMID: 37562076 .
Alaoui L, Villar J, Leclere R, Le Gallou S, Relouzat F, Michaud HA, Tarte K, Teissier N, Favier B, Roussel M, Segura E. Functional specialization of short-lived and long-lived macrophage subsets in human tonsils. J Exp Med. 2023; Jul 3;220(7):e20230002. Epub 2023 Apr 10. doi: 10.1084/jem.20230002. PMID: 37036425 ; PMCID: PMC10098144.
Villar J, Cros A, De Juan A, Alaoui L, Bonte PE, Lau CM, Tiniakou I, Reizis B, Segura E. ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment. Nat Immunol. 2023; Jan;24(1):84-95. Epub 2022 Dec 21. doi: 10.1038/s41590-022-01374-0. PMID: 36543959 ; PMCID: PMC9810530.
Tohme M, Maisonneuve L, Achour K, Dussiot M, Maschalidi S, Manoury B. TLR7 trafficking and signaling in B cells is regulated by the MHCII-associated invariant chain. J Cell Sci. 2021; Oct 15;134(20). doi: 10.1242/jcs.236711. PMID: 32079661 .
Maatouk L, Compagnion AC, Sauvage MC, Bemelmans AP, Leclere-Turbant S, Cirotteau V, Tohme M, Beke A, Trichet M, Bazin V, Trawick BN, Ransohoff RM, Tronche F, Manoury B, Vyas S. TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons. Nat Commun. 2018 Jun 22;9(1):2450. doi: 10.1038/s41467-018-05680-w. PMID: 30068993 ; PMCID: PMC6070486.
Maschalidi S, Nunes-Hasler P, Nascimento CR, Sallent I, Lannoy V, Garfa-Traore M, Cagnard N, Sepulveda FE, Vargas P, Lennon-Duménil AM, van Endert P, Capiod T, Demaurex N, Darrasse-Jèze G, Manoury B. UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells. Nat Commun. 2017; Nov 21;8(1):1640. doi: 10.1038/s41467-017-01601-5. PMID: 29158474 ; PMCID: PMC5696382.
Funding and grants