Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
J Immunol. 2011 Aug 1;187(3):1235-42. doi: 10.4049/jimmunol.1100270. Epub 2011 Jun 27.
The development of invariant NKT (iNKT) cells depends on the thymus. After positive selection by CD4(+)CD8(+)CD1d(+) cortical thymocytes, iNKT cells proceed from CD44(low)NK1.1(-) (stage 1) to CD44(high)NK1.1(-) (stage 2), and then to CD44(high)NK1.1(+) (stage 3) cells. The programming of cytokine production occurs along the three differentiation stages, whereas the acquisition of NK receptors occurs at stage 3. Stage 3 thymic iNKT cells are specifically reduced in Il15ra(-/-) mice. The mechanism underlying this homeostatic deficiency and whether the IL-15 system affects other thymic iNKT cell developmental events remain elusive. In this study, we demonstrate that increased cell death contributed to the reduction of stage 3 cells in Il15ra(-/-) mice, as knockout of Bim restored this population. IL-15-dependent upregulation of Bcl-2 in stage 3 cells affected cell survival, as overexpression of hBcl-2 partially restored stage 3 cells in Il15ra(-/-) mice. Moreover, thymic iNKT cells in Il15ra(-/-) mice were impaired in functional maturation, including the acquisition of Ly49 and NKG2 receptors and the programming of cytokine production. Finally, IL-15Rα expressed by radiation-resistant cells is necessary and sufficient to support the survival as well as the examined maturation events of thymic iNKT cells.
固有自然杀伤 T(iNKT)细胞的发育依赖于胸腺。在经过 CD4(+)CD8(+)CD1d(+)皮质胸腺细胞的阳性选择后，iNKT 细胞从 CD44(low)NK1.1(-)(阶段 1)进展为 CD44(high)NK1.1(-)(阶段 2)，然后是 CD44(high)NK1.1(+) (阶段 3)细胞。细胞因子产生的编程发生在这三个分化阶段，而 NK 受体的获得发生在第 3 阶段。第 3 阶段胸腺 iNKT 细胞在 Il15ra(-/-)小鼠中特异性减少。这种动态平衡缺陷的机制以及 IL-15 系统是否影响其他胸腺 iNKT 细胞发育事件仍不清楚。在这项研究中，我们证明细胞死亡增加导致 Il15ra(-/-)小鼠中第 3 阶段细胞减少，因为 Bim 的敲除恢复了该群体。IL-15 依赖性上调第 3 阶段细胞中的 Bcl-2 影响细胞存活，因为 hBcl-2 的过表达部分恢复了 Il15ra(-/-)小鼠中的第 3 阶段细胞。此外，Il15ra(-/-)小鼠中的胸腺 iNKT 细胞在功能成熟方面受损，包括 Ly49 和 NKG2 受体的获得以及细胞因子产生的编程。最后，辐射抗性细胞表达的 IL-15Rα是支持胸腺 iNKT 细胞存活以及所检查的成熟事件所必需和充分的。
