PMID- 23675302
OWN - NLM
STAT- MEDLINE
DCOM- 20130920
LR  - 20220129
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 9
IP  - 5
DP  - 2013 May
TI  - LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-gamma production by repressing 
      beta-catenin activation in dendritic cells.
PG  - e1003357
LID - 10.1371/journal.ppat.1003357 [doi]
LID - e1003357
AB  - 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.
FAU - Orr, Selinda J
AU  - Orr SJ
AD  - Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, 
      Maryland, United States of America.
FAU - Burg, Ashley R
AU  - Burg AR
FAU - Chan, Tim
AU  - Chan T
FAU - Quigley, Laura
AU  - Quigley L
FAU - Jones, Gareth W
AU  - Jones GW
FAU - Ford, Jill W
AU  - Ford JW
FAU - Hodge, Deborah
AU  - Hodge D
FAU - Razzook, Catherine
AU  - Razzook C
FAU - Sarhan, Joseph
AU  - Sarhan J
FAU - Jones, Yava L
AU  - Jones YL
FAU - Whittaker, Gillian C
AU  - Whittaker GC
FAU - Boelte, Kimberly C
AU  - Boelte KC
FAU - Lyakh, Lyudmila
AU  - Lyakh L
FAU - Cardone, Marco
AU  - Cardone M
FAU - O'Connor, Geraldine M
AU  - O'Connor GM
FAU - Tan, Cuiyan
AU  - Tan C
FAU - Li, Hongchuan
AU  - Li H
FAU - Anderson, Stephen K
AU  - Anderson SK
FAU - Jones, Simon A
AU  - Jones SA
FAU - Zhang, Weiguo
AU  - Zhang W
FAU - Taylor, Philip R
AU  - Taylor PR
FAU - Trinchieri, Giorgio
AU  - Trinchieri G
FAU - McVicar, Daniel W
AU  - McVicar DW
LA  - eng
GR  - G0601617/MRC_/Medical Research Council/United Kingdom
GR  - 18286/VAC_/Versus Arthritis/United Kingdom
GR  - ImNIH/Intramural NIH HHS/United States
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - 18286/ARC_/Arthritis Research UK/United Kingdom
GR  - 099953/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130509
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (Amino Acid Transport System y+)
RN  - 0 (Fusion Regulatory Protein 1, Light Chains)
RN  - 0 (Lectins, C-Type)
RN  - 0 (SLC7A8 protein, mouse)
RN  - 0 (beta Catenin)
RN  - 187348-17-0 (Interleukin-12)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Amino Acid Transport System y+/*immunology/metabolism
MH  - Animals
MH  - Candidiasis/*immunology/metabolism
MH  - Dendritic Cells/*immunology/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Fusion Regulatory Protein 1, Light Chains/*immunology/metabolism
MH  - Interferon-gamma/biosynthesis/immunology
MH  - Interleukin-12/biosynthesis/immunology
MH  - Lectins, C-Type/*immunology/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/immunology
MH  - beta Catenin/*immunology/metabolism
PMC - PMC3649983
COIS- The authors have declared that no competing interests exist.
EDAT- 2013/05/16 06:00
MHDA- 2013/09/21 06:00
PMCR- 2013/05/09
CRDT- 2013/05/16 06:00
PHST- 2012/08/29 00:00 [received]
PHST- 2013/03/27 00:00 [accepted]
PHST- 2013/05/16 06:00 [entrez]
PHST- 2013/05/16 06:00 [pubmed]
PHST- 2013/09/21 06:00 [medline]
PHST- 2013/05/09 00:00 [pmc-release]
AID - PPATHOGENS-D-12-02126 [pii]
AID - 10.1371/journal.ppat.1003357 [doi]
PST - ppublish
SO  - PLoS Pathog. 2013 May;9(5):e1003357. doi: 10.1371/journal.ppat.1003357. Epub 2013 
      May 9.