title: LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.
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.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.
authors.forename: Selinda J
authors.initials: SJ
authors.lastname: Orr
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Burg
authors.forename: Tim
authors.initials: T
authors.lastname: Chan
authors.forename: Laura
authors.initials: L
authors.lastname: Quigley
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.forename: Jill W
authors.initials: JW
authors.lastname: Ford
authors.forename: Deborah
authors.initials: D
authors.lastname: Hodge
authors.forename: Catherine
authors.initials: C
authors.lastname: Razzook
authors.forename: Joseph
authors.initials: J
authors.lastname: Sarhan
authors.forename: Yava L
authors.initials: YL
authors.lastname: Jones
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Whittaker
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Boelte
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Lyakh
authors.forename: Marco
authors.initials: M
authors.lastname: Cardone
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: O'Connor
authors.forename: Cuiyan
authors.initials: C
authors.lastname: Tan
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Li
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Anderson
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
mesh_terms: D027182:Amino Acid Transport System y+ / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002177:Candidiasis / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D027301:Fusion Regulatory Protein 1, Light Chains / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051176:beta Catenin / Q000276:immunology* / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D027301:Fusion Regulatory Protein 1, Light Chains; D037181:Lectins, C-Type; C518286:SLC7A8 protein, mouse; D051176:beta Catenin; D018664:Interleukin-12; D007371:Interferon-gamma