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LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells

Orr, Selinda Jane, Burg, Ashley R., Chan, Tim, Quigley, Laura, Jones, Gareth Wyn, Ford, Jill W., Hodge, Deborah, Razzook, Catherine, Sarhan, Joseph, Jones, Yava L., Whittaker, Gillian C., Boelte, Kimberly C., Lyakh, Lyudmila, Cardone, Marco, O'Connor, Geraldine M., Tan, Cuiyan, Li, Hongchuan, Anderson, Stephen K., Jones, Simon Arnett, Zhang, Weiguo, Taylor, Philip Russel, Trinchieri, Giorgio and McVicar, Daniel W. 2013. LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. PLoS Pathogens 9 (5) , e1003357. 10.1371/journal.ppat.1003357

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Abstract

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2−/− mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2−/− DCs. Accordingly, Lat2−/− DCs directed reduced Th1 polarization in vitro and Lat2−/− mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
Publisher: Public Library of Science
ISSN: 1553-7374
Funders: Medical Research Council UK (MRC) (G0601617)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 14 Jul 2019 00:04
URI: http://orca.cf.ac.uk/id/eprint/48539

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