Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2021 May 14;12:642856. doi: 10.3389/fimmu.2021.642856. eCollection 2021.
Invariant NKT (NKT) cells are thymus-generated innate-like T cells, comprised of three distinct subsets with divergent effector functions. The molecular mechanism that drives the lineage trifurcation of immature NKT cells into the NKT1, NKT2, and NKT17 subsets remains a controversial issue that remains to be resolved. Because cytokine receptor signaling is necessary for NKT cell generation, cytokines are proposed to contribute to NKT subset differentiation also. However, the precise roles and requirements of cytokines in these processes are not fully understood. Here, we show that IL-2Rβ, a nonredundant component of the IL-15 receptor complex, plays a critical role in both the development and differentiation of thymic NKT cells. While the induction of IL-2Rβ expression on postselection thymocytes is necessary to drive the generation of NKT cells, surprisingly, premature IL-2Rβ expression on immature NKT cells was detrimental to their development. Moreover, while IL-2Rβ is necessary for NKT1 generation, paradoxically, we found that the increased abundance of IL-2Rβ suppressed NKT1 generation without affecting NKT2 and NKT17 cell differentiation. Thus, the timing and abundance of IL-2Rβ expression control NKT lineage fate and development, thereby establishing cytokine receptor expression as a critical regulator of thymic NKT cell differentiation.
不变自然杀伤 T（NKT）细胞是胸腺生成的先天样 T 细胞，由三个具有不同效应功能的不同亚群组成。驱动未成熟 NKT 细胞谱系三分叉为 NKT1、NKT2 和 NKT17 亚群的分子机制仍然是一个有争议的问题，有待解决。由于细胞因子受体信号对于 NKT 细胞的产生是必需的，因此细胞因子也被认为有助于 NKT 亚群分化。然而，细胞因子在这些过程中的精确作用和要求尚不完全清楚。在这里，我们表明 IL-2Rβ，IL-15 受体复合物的非冗余组成部分，在胸腺 NKT 细胞的发育和分化中起着关键作用。虽然诱导选择后胸腺细胞上的 IL-2Rβ 表达对于驱动 NKT 细胞的产生是必需的，但令人惊讶的是，未成熟 NKT 细胞上过早的 IL-2Rβ 表达对其发育有害。此外，虽然 IL-2Rβ 对于 NKT1 的产生是必需的，但矛盾的是，我们发现 IL-2Rβ 的丰度增加抑制了 NKT1 的产生，而不影响 NKT2 和 NKT17 细胞的分化。因此，IL-2Rβ 表达的时间和丰度控制 NKT 谱系命运和发育，从而确立细胞因子受体表达作为胸腺 NKT 细胞分化的关键调节剂。
