Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
J Immunol. 2011 Jan 15;186(2):838-47. doi: 10.4049/jimmunol.1001735. Epub 2010 Dec 10.
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.
固有自然杀伤 T(iNKT)细胞激活后的命运仍存在争议，并不明确。我们系统性地研究了 iNKT 细胞在分别经 TCR 依赖性和非依赖性激活（用 α-半乳糖神经酰胺[αGC]或 IL-18 联合 IL-12）后是如何被调控的。我们的研究揭示，αGC 或 IL-18 联合 IL-12 的激活会导致肝脏中 iNKT 细胞的短暂耗竭，这种耗竭与半胱天冬酶 3（caspase 3）介导的细胞凋亡无关。iNKT 细胞耗竭后，通过不同的机制，出现表型不同的细胞进行再增殖和扩增。αGC 而非 IL-18 联合 IL-12 处理后肝脏 iNKT 细胞的扩增需要完整的脾脏和 IFN-γ。此外，与 αGC 相比，IL-18 联合 IL-12 诱导了肝脏 iNKT 细胞更持久的扩增。αGC 处理后再增殖到肝脏的 iNKT 细胞具有更高水平的抑制性受体 PD-1 和 Lag3，而 IL-18 联合 IL-12 处理后再增殖到肝脏的 iNKT 细胞具有更高水平的 TCR 和 ICOS。与导致 iNKT 细胞短暂耗竭的急性处理相反，慢性 αGC 或 IL-18 联合 IL-12 处理会导致长期的系统性耗竭，需要完整的胸腺才能使肝脏中的 iNKT 细胞得到再增殖。本报告揭示了肝脏在激活的 iNKT 细胞耗竭中的一个以前未定义的作用。此外，TCR 依赖性和非依赖性激活可差异化地调控 iNKT 细胞的分布和表型。这些结果为理解 iNKT 细胞在激活后如何被系统性调控提供了新的见解。
