Transcriptional regulator Id2 controls survival of hepatic NKT cells.
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-X(L), 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.
Monticelli
Laurel A
LA
Division of Biology, University of California San Diego, La Jolla, CA 92093-0377, USA.
Yang
Yang
Y
Knell
Jamie
J
D'Cruz
Louise M
LM
Cannarile
Michael A
MA
Engel
Isaac
I
Kronenberg
Mitchell
M
Goldrath
Ananda W
AW
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D054387:Receptors, CXCR / Q000096:biosynthesis; D000075744:Receptors, CXCR6; D051020:bcl-X Protein / Q000096:biosynthesis
C494812:Bcl2l1 protein, mouse; C482906:Cxcr6 protein, mouse; D016207:Cytokines; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D051020:bcl-X Protein; C052617:Bcl2 protein, mouse