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LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.

Orr SJ, Burg AR, Chan T, Quigley L, Jones GW, Ford JW, Hodge D, Razzook C, Sarhan J, Jones YL, Whittaker GC, Boelte KC, Lyakh L, Cardone M, O'Connor GM, Tan C, Li H, Anderson SK, Jones SA, Zhang W, Taylor PR, Trinchieri G, McVicar DW - PLoS Pathog. (2013)

Bottom Line: 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.Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.

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.

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Lat2−/− mice display increased susceptibility to C. albicans.Survival curves of WT (filled squares) and Lat2−/− mice (filled circles) infected intravenously with (A) 1.5×105 CFU or (B) 5×104 CFU C. albicans SC5314. (A) Graph is representative of 3 independent experiments. p = 0.04 (log-rank test), n = 10. (B) Graph is the cumulative result of 3 independent experiments. p = 0.04 (log-rank test), n = 30. (C) CFU in the kidneys at 9 days after infection with 1.5×105 CFU C. albicans. Graph is the cumulative result of 4 independent experiments. *p<0.05 (Student's t test on transformed data). Each symbol represents an individual mouse. (D) Fungal growth in a representative WT (left panel (2× magnification)) or Lat2−/− (middle panel (2x) and enlargement of boxed area, right panel (20x)) kidney at time of death (Lat2−/−) or 55 days (WT) after i.v. infection with 5×104 CFU C. albicans. Kidney sections were stained with Periodic Acid Schiff.
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ppat-1003357-g001: Lat2−/− mice display increased susceptibility to C. albicans.Survival curves of WT (filled squares) and Lat2−/− mice (filled circles) infected intravenously with (A) 1.5×105 CFU or (B) 5×104 CFU C. albicans SC5314. (A) Graph is representative of 3 independent experiments. p = 0.04 (log-rank test), n = 10. (B) Graph is the cumulative result of 3 independent experiments. p = 0.04 (log-rank test), n = 30. (C) CFU in the kidneys at 9 days after infection with 1.5×105 CFU C. albicans. Graph is the cumulative result of 4 independent experiments. *p<0.05 (Student's t test on transformed data). Each symbol represents an individual mouse. (D) Fungal growth in a representative WT (left panel (2× magnification)) or Lat2−/− (middle panel (2x) and enlargement of boxed area, right panel (20x)) kidney at time of death (Lat2−/−) or 55 days (WT) after i.v. infection with 5×104 CFU C. albicans. Kidney sections were stained with Periodic Acid Schiff.

Mentions: As LAB has previously been shown to mediate/regulate signaling and/or cytokine responses downstream of ITAM-coupled receptors and TLRs [23], [24], we hypothesized that LAB would play a role in anti-fungal immunity. To investigate this possibility, we systemically infected WT and Lat2−/− mice with C. albicans. Lat2−/− mice displayed increased susceptibility to high (1.5×105) and low (5×104) dose C. albicans infection compared to WT mice (Fig. 1A–B). The reduced survival was paralleled by increased fungal burden in the kidneys of Lat2−/− mice, nine days after infection (i.v.) with C. albicans (Fig. 1C). The kidney depicted from a Lat2−/− mouse that succumbed to infection displays a marked proliferation of fungal hyphae within the pelvis, which was surrounded by neutrophilic inflammation, consistent with an inability to clear the infection (Fig. 1D). Together, these data demonstrate that LAB is important for the host response to C. albicans infection.


LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-γ production by repressing β-catenin activation in dendritic cells.

Orr SJ, Burg AR, Chan T, Quigley L, Jones GW, Ford JW, Hodge D, Razzook C, Sarhan J, Jones YL, Whittaker GC, Boelte KC, Lyakh L, Cardone M, O'Connor GM, Tan C, Li H, Anderson SK, Jones SA, Zhang W, Taylor PR, Trinchieri G, McVicar DW - PLoS Pathog. (2013)

Lat2−/− mice display increased susceptibility to C. albicans.Survival curves of WT (filled squares) and Lat2−/− mice (filled circles) infected intravenously with (A) 1.5×105 CFU or (B) 5×104 CFU C. albicans SC5314. (A) Graph is representative of 3 independent experiments. p = 0.04 (log-rank test), n = 10. (B) Graph is the cumulative result of 3 independent experiments. p = 0.04 (log-rank test), n = 30. (C) CFU in the kidneys at 9 days after infection with 1.5×105 CFU C. albicans. Graph is the cumulative result of 4 independent experiments. *p<0.05 (Student's t test on transformed data). Each symbol represents an individual mouse. (D) Fungal growth in a representative WT (left panel (2× magnification)) or Lat2−/− (middle panel (2x) and enlargement of boxed area, right panel (20x)) kidney at time of death (Lat2−/−) or 55 days (WT) after i.v. infection with 5×104 CFU C. albicans. Kidney sections were stained with Periodic Acid Schiff.
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ppat-1003357-g001: Lat2−/− mice display increased susceptibility to C. albicans.Survival curves of WT (filled squares) and Lat2−/− mice (filled circles) infected intravenously with (A) 1.5×105 CFU or (B) 5×104 CFU C. albicans SC5314. (A) Graph is representative of 3 independent experiments. p = 0.04 (log-rank test), n = 10. (B) Graph is the cumulative result of 3 independent experiments. p = 0.04 (log-rank test), n = 30. (C) CFU in the kidneys at 9 days after infection with 1.5×105 CFU C. albicans. Graph is the cumulative result of 4 independent experiments. *p<0.05 (Student's t test on transformed data). Each symbol represents an individual mouse. (D) Fungal growth in a representative WT (left panel (2× magnification)) or Lat2−/− (middle panel (2x) and enlargement of boxed area, right panel (20x)) kidney at time of death (Lat2−/−) or 55 days (WT) after i.v. infection with 5×104 CFU C. albicans. Kidney sections were stained with Periodic Acid Schiff.
Mentions: As LAB has previously been shown to mediate/regulate signaling and/or cytokine responses downstream of ITAM-coupled receptors and TLRs [23], [24], we hypothesized that LAB would play a role in anti-fungal immunity. To investigate this possibility, we systemically infected WT and Lat2−/− mice with C. albicans. Lat2−/− mice displayed increased susceptibility to high (1.5×105) and low (5×104) dose C. albicans infection compared to WT mice (Fig. 1A–B). The reduced survival was paralleled by increased fungal burden in the kidneys of Lat2−/− mice, nine days after infection (i.v.) with C. albicans (Fig. 1C). The kidney depicted from a Lat2−/− mouse that succumbed to infection displays a marked proliferation of fungal hyphae within the pelvis, which was surrounded by neutrophilic inflammation, consistent with an inability to clear the infection (Fig. 1D). Together, these data demonstrate that LAB is important for the host response to C. albicans infection.

Bottom Line: 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.Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.

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.

Show MeSH
Related in: MedlinePlus