title: TCR-dependent and -independent activation underlie liver-specific regulation of NKT cells.
abstract: The fate of invariant NKT (iNKT) cells following activation remains controversial and unclear. We systemically examined how iNKT cells are regulated following TCR-dependent and -independent activation with α-galactosylceramide (αGC) or IL-18 plus IL-12, respectively. Our studies reveal activation by αGC or IL-18 plus IL-12 induced transient depletion of iNKT cells exclusively in the liver that was independent of caspase 3-mediated apoptosis. The loss of iNKT cells was followed by repopulation and expansion of phenotypically distinct cells via different mechanisms. Liver iNKT cell expansion following αGC, but not IL-18 plus IL-12, treatment required an intact spleen and IFN-γ. Additionally, IL-18 plus IL-12 induced a more prolonged expansion of liver iNKT cells compared with αGC. iNKT cells that repopulate the liver following αGC had higher levels of suppressive receptors PD-1 and Lag3, whereas those that repopulate the liver following IL-18 plus IL-12 had increased levels of TCR and ICOS. In contrast to acute treatment that caused a transient loss of iNKT cells, chronic αGC or IL-18 plus IL-12 treatment caused long-term systemic loss requiring an intact thymus for repopulation of the liver. This report reveals a previously undefined role for the liver in the depletion of activated iNKT cells. Additionally, TCR-dependent and -independent activation differentially regulate iNKT cell distribution and phenotype. These results provide new insights for understanding how iNKT cells are systemically regulated following activation.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Subleski
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Hall
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Wolfe
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Scarzello
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Tim
authors.initials: T
authors.lastname: Chan
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Hodge
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Back
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D005699:Galactosylceramides / Q000502:physiology; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion / Q000379:methods; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D005699:Galactosylceramides; D020382:Interleukin-18; D011948:Receptors, Antigen, T-Cell; C493154:alpha-galactosylceramide; D018664:Interleukin-12; C505409:Casp3 protein, mouse; D053148:Caspase 3