Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, United States of America.
PLoS One. 2013 Sep 20;8(9):e76216. doi: 10.1371/journal.pone.0076216. eCollection 2013.
NF-κB inducing kinase (NIK, MAP3K14) is a key signaling molecule in non-canonical NF-κB activation, and NIK deficient mice have been instrumental in deciphering the immunologic role of this pathway. Global ablation of NIK prevents lymph node development, impairs thymic stromal development, and drastically reduces B cells. Despite altered thymic selection, T cell numbers are near normal in NIK deficient mice. The exception is CD4(+) regulatory T cells (Tregs), which are reduced in the thymus and periphery. Defects in thymic stroma are known to contribute to impaired Treg generation, but whether NIK also plays a cell intrinsic role in Tregs is unknown. Here, we compared intact mice with single and mixed BM chimeric mice to assess the intrinsic role of NIK in Treg generation and maintenance. We found that while NIK expression in stromal cells suffices for normal thymic Treg development, NIK is required cell-intrinsically to maintain peripheral Tregs. In addition, we unexpectedly discovered a cell-intrinsic role for NIK in memory phenotype conventional T cells that is masked in intact mice, but revealed in BM chimeras. These results demonstrate a novel role for NIK in peripheral regulatory and memory phenotype T cell homeostasis.
核因子-κB 诱导激酶（NIK，MAP3K14）是非经典 NF-κB 激活中的关键信号分子，而缺乏 NIK 的小鼠在阐明该途径的免疫学作用方面发挥了重要作用。NIK 的全局缺失可防止淋巴结发育，损害胸腺基质发育，并大大减少 B 细胞。尽管胸腺选择发生改变，但 NIK 缺陷小鼠中的 T 细胞数量接近正常。例外是 CD4(+)调节性 T 细胞（Tregs），其在胸腺和外周组织中减少。已知胸腺基质的缺陷会导致 Treg 生成受损，但 NIK 是否在 Tregs 中也发挥细胞内作用尚不清楚。在这里，我们比较了完整小鼠与单一和混合 BM 嵌合小鼠，以评估 NIK 在 Treg 生成和维持中的内在作用。我们发现，虽然基质细胞中的 NIK 表达足以维持正常的胸腺 Treg 发育，但 NIK 确实需要内在地维持外周 Tregs。此外，我们出人意料地发现 NIK 在记忆表型常规 T 细胞中具有细胞内作用，而在完整小鼠中被掩盖，但在 BM 嵌合小鼠中被揭示。这些结果表明 NIK 在调节性和记忆表型外周 T 细胞稳态中具有新的作用。
