Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
J Exp Med. 2013 Jun 3;210(6):1079-86. doi: 10.1084/jem.20122135. Epub 2013 May 6.
TCR signaling is a prerequisite for early stage development of invariant natural killer T (iNKT) cells, whereas IL-15 signaling is required for expansion and maturation at later stages. In this study, we show that TNF receptor associated factor 3 (TRAF3) plays a critical role in the transition between these two distinct signaling pathways and developmental stages. TRAF3-deficient iNKT cells in CD4(Cre)TRAF3(flox/flox) (T-TRAF3(-/-)) mice exhibit defective up-regulation of T-bet and CD122, two critical molecules for IL-15 signaling, and as a consequence, IL-15-mediated iNKT cell proliferation and survival are impaired. Consistently, development of iNKT cells in T-TRAF3(-/-) mice shows a major defect at developmental stages 2 and 3, but not stages 0 and 1. We further demonstrated that defective T-bet up-regulation occurring during the stage 1 to stage 2 transition results from reduced TCR signaling in TRAF3(-/-) iNKT cells. In addition, mature TRAF3(-/-) iNKT cells displayed defective cytokine responses upon TCR stimulation. Collectively, our results reveal that by modulating the relative strength of TCR signaling, TRAF3 is an important regulator of iNKT cell development and functions.
TCR 信号是先天自然杀伤 T(iNKT)细胞早期发育的必要条件，而 IL-15 信号则是后期扩张和成熟所必需的。在这项研究中，我们表明 TNF 受体相关因子 3(TRAF3)在这两种不同的信号通路和发育阶段之间的转变中起着关键作用。在 CD4(Cre)TRAF3(flox/flox) (T-TRAF3(-/-)) 小鼠中缺乏 TRAF3 的 iNKT 细胞表现出 T 细胞因子激活因子 3 和 CD122 的上调缺陷，这是 IL-15 信号的两个关键分子，因此，IL-15 介导的 iNKT 细胞增殖和存活受损。一致地，T-TRAF3(-/-) 小鼠中的 iNKT 细胞发育在发育阶段 2 和 3 显示出主要缺陷，但在阶段 0 和 1 则没有。我们进一步证明，在阶段 1 到阶段 2 的过渡期间发生的 T-bet 上调缺陷是由于 TRAF3(-/-)iNKT 细胞中 TCR 信号的减少。此外，成熟的 TRAF3(-/-)iNKT 细胞在 TCR 刺激下表现出缺陷的细胞因子反应。总之，我们的结果表明，通过调节 TCR 信号的相对强度，TRAF3 是 iNKT 细胞发育和功能的重要调节剂。
