Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 46, Pages 19461-19466Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0908249106
Keywords
E protein; homeostasis; Inhibitor of DNA binding; transcription factor
Categories
Funding
- Cancer Research Institute
- Pew Scholar Award
- National Institutes of Health [R37 AI71922]
- University of California San Diego, Center for Molecular Genetics
- Deutsche Forschungsgemeinschaft [CA 715/1-1]
- Leukemia Lymphoma Society
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Natural killer T cells expressing an invariant T-cell receptor ( iNKT) regulate activation of both innate and adaptive immunity in many contexts. iNKT cells accumulate in the liver and rapidly produce prodigious amounts of numerous cytokines upon activation, impacting the immune response to viral infection, immunosurveillance for malignant cells, and liver regeneration. However, little is known about the factors controlling iNKT homeostasis, survival and hepatic localization. Here, we report that the absence of the transcriptional regulator Id2 resulted in a severe, intrinsic defect in the accumulation of hepatic iNKT cells. Id2-deficient iNKT cells showed increased cell death in the liver, although migration and functional activity were not impaired in comparison to Id2-expressing iNKT cells. Id2-deficient iNKT cells exhibited diminished expression of CXCR6, a critical determinant of iNKT cell accumulation in the liver, and of the anti-apoptotic molecules bcl-2 and bcl-XL, compared to Id2-sufficient iNKT cells. Furthermore, survival and accumulation of iNKT cells lacking Id2 expression was rescued by deficiency in bim, a key pro-apoptotic molecule. Thus, Id2 was necessary to establish a hepatic iNKT cell population, defining a role for Id2 and implicating the Id targets, E protein transcription factors, in the regulation of iNKT cell homeostasis.
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