Defining the Signature of VISTA on Myeloid Cell Chemokine Responsiveness
Defining the Signature of VISTA on Myeloid Cell Chemokine Responsiveness
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DOI：
10.3389/fimmu.2019.02641
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发表时间：
2019-11-19
影响因子：
7.3
通讯作者：
Lines, J. Louise
中科院分区：
文献类型：
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作者：
Broughton, Thomas W. K.;ElTanbouly, Mohamed A.;Lines, J. Louise
负检查点调节因子（NCR）在人类健康和疾病中的作用怎么强调都不为过。含V结构域Ig的T细胞活化抑制因子（VISTA）是一种主要在造血区室中表达的IG超家族蛋白，并且已经研究了其在T细胞应答的负调节中的作用。本研究中呈现的结果表明，与所有其他NCR不同，VISTA缺陷显著影响巨噬细胞细胞因子和趋化因子的产生，以及VISTA缺陷巨噬细胞的趋化反应。一组选定的炎性趋化因子，包括CCL2、CCL3、CCL4和CCL5，在VISTA KO巨噬细胞的培养上清液中显著升高。VISTA缺乏也改变了趋化因子受体再循环，并严重破坏了骨髓趋化性。VISTA缺乏对体内趋化性的影响是明显的，KO巨噬细胞和MDSC迁移到肿瘤微环境的能力降低。这是NCR影响骨髓介质产生和趋化性的首次证明，并将指导使用抗VISTA治疗剂来操纵炎性疾病和癌症中炎性巨噬细胞或免疫抑制性MDSC的趋化性。
The role of negative checkpoint regulators (NCRs) in human health and disease cannot be overstated. V-domain Ig-containing Suppressor of T-cell Activation (VISTA) is an Ig superfamily protein predominantly expressed within the hematopoietic compartment and has been studied for its role in the negative regulation of T cell responses. The findings presented in this study show that, unlike all other NCRs, VISTA deficiency dramatically impacts on macrophage cytokine and chemokine production, as well as the chemotactic response of VISTA-deficient macrophages. A select group of inflammatory chemokines, including CCL2, CCL3, CCL4, and CCL5, was strikingly elevated in culture supernatants from VISTA KO macrophages. VISTA deficiency also altered chemokine receptor recycling and profoundly disrupted myeloid chemotaxis. The impact of VISTA deficiency on chemotaxis in vivo was apparent with the reduced ability of both KO macrophages and MDSCs to migrate to the tumor microenvironment. This is the first demonstration of an NCR impacting on myeloid mediator production and chemotaxis, and will guide the use of anti-VISTA therapeutics to manipulate the chemotaxis of inflammatory macrophages or immunosuppressive MDSCs in inflammatory diseases and cancer.