Laboratory of Immune Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sci Immunol. 2022 Oct 28;7(76):eabj8760. doi: 10.1126/sciimmunol.abj8760. Epub 2022 Oct 21.
Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244CXCR6), C1 (CD244CXCR6), or C2 (CD244CXCR6) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244CXCR6 iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.
固有自然杀伤 T(iNKT)细胞是一群识别脂质抗原的先天样 T 淋巴细胞。它们被认为是组织驻留细胞，对全身和局部免疫调节很重要。为了研究 iNKT 细胞的异质性，我们重新描述了胸腺和外周组织中的 iNKT 细胞。通过表达自然杀伤细胞受体 CD244 和趋化因子受体 CXCR6，胸腺中的 iNKT 细胞分为三个亚群，分别命名为 C0（CD244CXCR6）、C1（CD244CXCR6）或 C2（CD244CXCR6）iNKT 细胞。C2 iNKT 细胞由 C0 iNKT 细胞发育和成熟，严格依赖于胸腺上皮细胞产生的 IL-15。C2 iNKT 细胞表达高水平的 IFN-γ 和颗粒酶，表现出更多的 NK 细胞样特征，而 C1 iNKT 细胞表现出更多的 T 细胞样特征。C2 iNKT 细胞受微生物组和衰老的影响，并抑制胸腺中自身免疫调节因子 AIRE 的表达。在外周组织中，循环的 C2 iNKT 细胞与传统的组织驻留 C1 iNKT 细胞不同。功能上，C2 iNKT 细胞通过增强抗肿瘤免疫来保护小鼠免受黑色素瘤细胞的肿瘤转移，并促进抗流感病毒感染的抗病毒免疫反应。此外，我们鉴定了具有高细胞毒性的人 CD244CXCR6 iNKT 细胞作为小鼠 C2 iNKT 细胞的对应物。因此，这项研究揭示了一种具有 NK 细胞样特性的循环 iNKT 细胞亚群，与传统的组织驻留 iNKT 细胞不同。
