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

Selinda Jane Orr, Ashley R. Burg, Tim Chan, Laura Quigley, Gareth Wyn Jones, Jill W. Ford, Deborah Hodge, Catherine Razzook, Joseph Sarhan, Yava L. Jones, Gillian C. Whittaker, Kimberly C. Boelte, Lyudmila Lyakh, Marco Cardone, Geraldine M. O'Connor, Cuiyan Tan, Hongchuan Li, Stephen K. Anderson, Simon Arnett Jones, Weiguo ZhangPhilip Russel Taylor, Giorgio Trinchieri, Daniel W. McVicar

Research output: Contribution to journalArticle (Academic Journal)

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 beta-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-gamma production in vivo/ex vivo. Thus our data define a novel link between LAB and beta-catenin nuclear accumulation in DCs that facilitates IFN-gamma 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-gamma response for pathogen clearance.
Original languageEnglish
Article numbere1003357
Number of pages15
JournalPLoS Pathogens
Volume9
Issue number5
DOIs
Publication statusPublished - 1 May 2013

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