LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.
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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.
author list (cited authors)
Orr, S. J., Burg, A. R., Chan, T., Quigley, L., Jones, G. W., Ford, J. W., ... McVicar, D. W.
complete list of authors
Orr, Selinda J||Burg, Ashley R||Chan, Tim||Quigley, Laura||Jones, Gareth W||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 A||Zhang, Weiguo||Taylor, Philip R||Trinchieri, Giorgio||McVicar, Daniel W