LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.
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 recepto...
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2013
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oai:doaj.org-article:144332c55da84330a2dc42ae2982cc572021-11-18T06:05:39ZLAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.1553-73661553-737410.1371/journal.ppat.1003357https://doaj.org/article/144332c55da84330a2dc42ae2982cc572013-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23675302/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Fungal 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.Selinda J OrrAshley R BurgTim ChanLaura QuigleyGareth W JonesJill W FordDeborah HodgeCatherine RazzookJoseph SarhanYava L JonesGillian C WhittakerKimberly C BoelteLyudmila LyakhMarco CardoneGeraldine M O'ConnorCuiyan TanHongchuan LiStephen K AndersonSimon A JonesWeiguo ZhangPhilip R TaylorGiorgio TrinchieriDaniel W McVicarPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 5, p e1003357 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Selinda J Orr Ashley R Burg Tim Chan Laura Quigley Gareth W 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 A Jones Weiguo Zhang Philip R Taylor Giorgio Trinchieri Daniel W McVicar LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. |
| description |
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. |
| format |
article |
| author |
Selinda J Orr Ashley R Burg Tim Chan Laura Quigley Gareth W 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 A Jones Weiguo Zhang Philip R Taylor Giorgio Trinchieri Daniel W McVicar |
| author_facet |
Selinda J Orr Ashley R Burg Tim Chan Laura Quigley Gareth W 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 A Jones Weiguo Zhang Philip R Taylor Giorgio Trinchieri Daniel W McVicar |
| author_sort |
Selinda J Orr |
| title |
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. |
| title_short |
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. |
| title_full |
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. |
| title_fullStr |
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. |
| title_full_unstemmed |
LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells. |
| title_sort |
lab/ntal facilitates fungal/pamp-induced il-12 and ifn-γ production by repressing β-catenin activation in dendritic cells. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/144332c55da84330a2dc42ae2982cc57 |
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