TCR-Dependent and -Independent Activation Underlie Liver-Specific Regulation of NKT Cells

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 alpha-galactosylceramide (alpha GC) or IL-18 plus IL-12, respectively. Our studies reveal activation by alpha GC 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 alpha GC, but not IL-18 plus IL-12, treatment required an intact spleen and IFN-gamma. Additionally, IL-18 plus IL-12 induced a more prolonged expansion of liver iNKT cells compared with alpha GC. iNKT cells that repopulate the liver following alpha GC 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 alpha GC 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. The Journal of Immunology, 2011, 186: 838-847.

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