| First Author | Orr SJ | Year | 2013 |
| Journal | PLoS Pathog | Volume | 9 |
| Issue | 5 | Pages | e1003357 |
| PubMed ID | 23675302 | Mgi Jnum | J:213405 |
| Mgi Id | MGI:5584276 | Doi | 10.1371/journal.ppat.1003357 |
| Citation | Orr SJ, et al. (2013) LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-gamma production by repressing beta-catenin activation in dendritic cells. PLoS Pathog 9(5):e1003357 |
| abstractText | 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. |
