Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity.
Cytotoxic granzyme C-expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity.
复制标题
DOI：
10.1126/sciimmunol.abi8642
复制
发表时间：
2022-04-08
影响因子：
24.8
通讯作者：
中科院分区：
文献类型：
--
作者：
先天淋巴细胞是细胞免疫系统的组成部分，它可以协调宿主防御多种挑战，当失调时触发免疫病理。自然杀伤细胞（NK）和先天淋巴样细胞（ILCs）是先天免疫效应器，被认为在功能上分别反映传统的细胞毒性T淋巴细胞和辅助T细胞。在这里，我们发现细胞溶解分子颗粒酶C在小鼠肝脏和唾液腺中具有1型ILCs （ILC1s）表型的细胞中表达。细胞命运定位和转移研究表明，表达颗粒酶c的先天淋巴细胞可以来源于ILC祖细胞，并且不与NK细胞、ILC2s或ILC3s相互转化。颗粒酶C定义了ILC1s的成熟状态。这些表达ILC1s的颗粒酶C需要转录因子T-bet，在较小程度上需要Eomes和转化生长因子-β (TGF-β)信号的支持才能在唾液腺中维持。在转基因小鼠乳腺癌模型中，消耗ILC1s导致肿瘤加速生长。白细胞介素-15 （IL-15）刺激后，ILC1s获得颗粒酶C表达，从而激活穿孔素介导的细胞毒性。在新生小鼠中，表达颗粒酶c的IL-15调控的转录因子Stat5的组成性激活可触发致死性穿孔依赖性自身免疫。因此，颗粒酶C标志着ILC1s的细胞毒性效应状态，扩大了它们的功能，而不是“帮手”淋巴细胞。ILC1s表达颗粒酶C，介导穿孔蛋白依赖性细胞毒性，并有助于自身免疫和癌症免疫监测。
Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we showed that the cytolytic molecule granzyme C was expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C-expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s. These granzyme C expressing ILC1s required the transcription factors T-bet and to a lesser extent Eomes and support from transforming growth factor-β (TGF-β) signaling for their maintenance in the salivary gland. In a transgenic mouse breast cancer model depleting ILC1s caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Constitutive activation of Stat5, a transcription factor regulated by IL-15, in granzyme C-expressing ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond ‘helper-like’ lymphocytes. ILC1s express granzyme C, mediate perforin-dependent cytotoxicity, and can contribute to autoimmunity and cancer immunosurveillance.
登录
查看更多内容
影响因子：
64.5
作者：
Fan X;Rudensky AY
通讯作者：
Rudensky AY
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
32.4
作者：
Bernink, Jochem H.;Krabbendam, Lisette;Spits, Hergen
通讯作者：
Spits, Hergen
DOI：
10.1073/pnas.1423244112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Constantinides, Michael G.;Gudjonson, Herman;Bendelac, Albert
通讯作者：
Bendelac, Albert
影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng