IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin.
IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin.
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DOI：
10.1084/jem.20180654
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发表时间：
2018-12-03
期刊：
影响因子：
--
通讯作者：
Lund AW
中科院分区：
文献类型：
--
作者：
Lane RS;Femel J;Breazeale AP;Loo CP;Thibault G;Kaempf A;Mori M;Tsujikawa T;Chang YH;Lund AW
莱恩等人。证明 IFNγ 诱导的非造血 PD-L1 抑制抗黑色素瘤免疫，并将淋巴管确定为反应的关键介质。他们证明，外周淋巴管充当组织驻留的免疫开关，可以平衡皮肤的保护性免疫和组织损伤。外周组织中的免疫抑制机制抵消保护性免疫以防止免疫病理，并被肿瘤利用来逃避免疫。虽然淋巴管促进 T 细胞启动，但它们也在稳态下对淋巴结发挥免疫抑制作用。因此，我们假设外周淋巴管获得抑制机制来限制局部效应 CD8+ T 细胞在小鼠皮肤中的积累。我们证明非造血 PD-L1 主要由淋巴和血液内皮细胞表达，并限制肿瘤微环境中 CD8+ T 细胞的积累。由组织浸润、抗原特异性 CD8+ T 细胞产生的 IFNγ 非常接近肿瘤相关淋巴管，足以诱导淋巴管 PD-L1 表达。通过淋巴特异性丢失 IFNγR 来破坏 IFNγ 依赖性串扰，可促进受感染和恶性皮肤中 T 细胞的积累，从而分别增强病毒病理学和肿瘤控制。因此，我们将 IFNγR 确定为淋巴管中的免疫开关，可平衡保护性免疫和免疫病理学，从而导致黑色素瘤的适应性免疫抵抗。
Lane et al. demonstrate that IFNγ-induced, nonhematopoietic PD-L1 suppresses anti-melanoma immunity and identify lymphatic vessels as key mediators of response. They demonstrate that peripheral lymphatic vessels act as tissue-resident, immunological switches that balance protective immunity and tissue damage in skin. Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments. IFNγ produced by tissue-infiltrating, antigen-specific CD8+ T cells, which are in close proximity to tumor-associated lymphatic vessels, is sufficient to induce lymphatic vessel PD-L1 expression. Disruption of IFNγ-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.
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DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
炎症引起的白细胞跨淋巴管内皮迁移的机制。
影响因子：
15.3
作者：
Johnson, Louise A;Clasper, Steven;Holt, Andrew P;Lalor, Patricia F;Baban, Dilair;Jackson, David G
通讯作者：
Jackson, David G
影响因子：
17.1
作者：
Fankhauser, Manuel;Broggi, Maria A. S.;Swartz, Melody A.
通讯作者：
Swartz, Melody A.
影响因子：
30.5
作者：
Bedoui, Sammy;Whitney, Paul G.;Heath, William R.
通讯作者：
Heath, William R.
影响因子：
32.4
作者：
Kataru, Raghu P.;Kim, Honsoul;Koh, Gou Young
通讯作者：
Koh, Gou Young