CD20; CD73; Co-stimulatory molecules; Cytokine; IL-10; α-galactosylceramide
Almishri W, Deans J, Swain MG. Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice. J Hepatol. 2015 Jun 18. pii: S0168-8278(15)00398-0. doi: 10.1016/j.jhep.2015.06.007. [Epub ahead of print]
BACKGROUND & AIMS:
Invariant natural killer T (iNKT) cells are present within the liver and have been implicated in the development of many liver diseases. Upon activation by glycolipid ligands (including α-galactosylceramide; αGalCer), hepatic iNKT cells produce numerous cytokines and recruit both pro-inflammatory and regulatory immune cells. However, the involvement of B cells in this process is poorly defined.
METHODS:
Wildtype (male, C57BL/6), B cell deficient, or B cell depleted mice were injected with αGalCer or vehicle and hepatic B cell phenotype and liver injury subsequently determined.
RESULTS:
iNKT cell activation resulted in liver injury and the rapid activation and hepatic recruitment of B cells (mainly innate-like B1 and MZ-like B cells) from the spleen and peritoneal cavity. B cells recruited to the liver produce IL-10 and TGFβ, and express cell surface CD73 (ectoenzyme which generates adenosine). B cell deficient mice developed augmented αGalCer-induced hepatitis, enhanced neutrophil recruitment and striking alterations in the hepatic cytokine milieu. αGalCer-induced hepatitis was unaltered in IL-10 -/- mice, or after TGFβ neutralization, but was significantly worsened in mice treated with a CD73 inhibitor.
CONCLUSIONS:
iNKT cell stimulation recruits innate-like regulatory B cells to the liver which suppress hepatic inflammation through IL-10 and TGFβ1 independent mechanisms, but involve CD73 activity. These findings highlight an important inflammation-suppressing role for B cells at early time points during the development of an innate immune response within the liver, and represent a potential therapeutic target for the treatment of liver disease.
BACKGROUND & AIMS:
Invariant natural killer T (iNKT) cells are present within the liver and have been implicated in the development of many liver diseases. Upon activation by glycolipid ligands (including α-galactosylceramide; αGalCer), hepatic iNKT cells produce numerous cytokines and recruit both pro-inflammatory and regulatory immune cells. However, the involvement of B cells in this process is poorly defined.
METHODS:
Wildtype (male, C57BL/6), B cell deficient, or B cell depleted mice were injected with αGalCer or vehicle and hepatic B cell phenotype and liver injury subsequently determined.
RESULTS:
iNKT cell activation resulted in liver injury and the rapid activation and hepatic recruitment of B cells (mainly innate-like B1 and MZ-like B cells) from the spleen and peritoneal cavity. B cells recruited to the liver produce IL-10 and TGFβ, and express cell surface CD73 (ectoenzyme which generates adenosine). B cell deficient mice developed augmented αGalCer-induced hepatitis, enhanced neutrophil recruitment and striking alterations in the hepatic cytokine milieu. αGalCer-induced hepatitis was unaltered in IL-10 -/- mice, or after TGFβ neutralization, but was significantly worsened in mice treated with a CD73 inhibitor.
CONCLUSIONS:
iNKT cell stimulation recruits innate-like regulatory B cells to the liver which suppress hepatic inflammation through IL-10 and TGFβ1 independent mechanisms, but involve CD73 activity. These findings highlight an important inflammation-suppressing role for B cells at early time points during the development of an innate immune response within the liver, and represent a potential therapeutic target for the treatment of liver disease.
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