Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
J Immunol. 2011 Dec 15;187(12):6335-45. doi: 10.4049/jimmunol.1003965. Epub 2011 Nov 14.
Semi-invariant NKT cells are thymus-derived innate-like lymphocytes that modulate microbial and tumor immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learned regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL-15-mediated thymic and peripheral NKT cell survival critically depended on Bcl-x(L) expression. Additionally, IL-15 regulated thymic developmental stage 2 to stage 3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic NKT cells. The loss of IL-15 also resulted in poor expression of key effector molecules such as IFN-γ, granzyme A and C, as well as several NK cell receptors, which are also regulated by T-bet in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-x(L), and effector differentiation, which is consistent with a role of T-bet in regulating terminal maturation.
半不变自然杀伤 T 细胞是一种来源于胸腺的先天样淋巴细胞,可调节微生物和肿瘤免疫以及自身免疫性疾病。这些 NKT 细胞的免疫调节特性是在其发育过程中获得的。关于促进 NKT 细胞发育的分子和细胞线索,已经有了很多了解,但这些细胞如何在胸腺和外周组织中维持以及如何获得功能能力,仍不完全清楚。我们发现,IL-15 在体外诱导胸腺和脾 NKT 细胞中几种 Bcl-2 家族存活因子的表达。然而,IL-15 介导的胸腺和外周 NKT 细胞存活严重依赖于 Bcl-x(L)的表达。此外,IL-15 调节胸腺发育阶段 2 到阶段 3 谱系进展和终末 NKT 细胞分化。全基因表达分析和验证表明,IL-15 调节胸腺 NKT 细胞中 Tbx21(T 细胞转录因子)的表达。IL-15 的缺失也导致 IFN-γ、颗粒酶 A 和 C 以及几种 NK 细胞受体等关键效应分子的表达不良,这些分子在 NKT 细胞中也受 T-bet 调节。总之,我们的研究结果表明,IL-15 在 NKT 细胞存活中起着关键作用,这种作用是通过 Bcl-x(L)介导的,在效应细胞分化中也起着关键作用,这与 T-bet 调节终末成熟的作用一致。