Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway.
Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway.
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DOI：
10.1016/j.ccr.2011.01.037
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发表时间：
2011-03-08
期刊：
影响因子：
50.3
通讯作者：
Bhardwaj N
中科院分区：
文献类型：
--
作者：
Godefroy E;Manches O;Dréno B;Hochman T;Rolnitzky L;Labarrière N;Guilloux Y;Goldberg J;Jotereau F;Bhardwaj N
基质金属蛋白酶-2（MMP-2）是一种降解细胞外基质的蛋白水解酶，在许多肿瘤中过度表达。在这里，我们记录了MMP-2特异性的CD 4 + T细胞在肿瘤浸润淋巴细胞（TIL）从黑色素瘤患者的存在。引人注目的是，MMP-2特异性CD 4 + T细胞显示炎性TH 2特征，即主要分泌TNFα、IL-4和IL-13并表达加塔-3。此外，MMP-2条件树突状细胞（DC）引发幼稚的CD 4 + T细胞分化成炎性TH 2表型通过OX 40 L表达和抑制IL-12 p70的生产。MMP-2降解I型IFN受体，从而阻止STAT 1磷酸化，这是IL-12 p35产生所必需的。因此，活性MMP-2作为内源性2型“调节剂”，并可能在观察到的黑色素瘤中有害的2型反应的患病率中发挥作用。几种黑素瘤相关抗原已经在免疫策略中被靶向以治疗黑素瘤患者。然而，这些方法的治疗效果仍然有限，表明迫切需要改进。由于MMP-2活性对黑色素瘤进展至关重要，因此它代表了疫苗治疗的一个有趣靶点。我们表明，MMP-2是一种免疫原性肿瘤抗原。然而，MMP-2特异性CD 4 + T淋巴细胞显示出次优的炎性TH 2特征。MMP-2-conditoned DC总理TH 2对几个黑色素瘤相关抗原（MAA）的反应，表明MMP-2可以创建一个TH 2倾斜的微环境中的旁观者的方式。阐明潜在的机制开辟了改善免疫应答的途径，以实现更有效的TH 1应答，并突出了MMP 2作为黑色素瘤靶抗原的潜力。
Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme degrading the extracellular matrix and over-expressed by many tumors. Here, we documented the presence of MMP-2-specific CD4+ T cells in tumor-infiltrating lymphocytes (TILs) from melanoma patients. Strikingly, MMP-2-specific CD4+ T cells displayed an inflammatory TH2 profile, i.e. mainly secreting TNFα, IL-4 and IL-13 and expressing GATA-3. Furthermore, MMP-2-conditioned dendritic cells (DCs) primed naïve CD4+ T cells to differentiate into an inflammatory TH2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 degrades the type-I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production. Active MMP-2, therefore, acts as an endogenous type-2 “conditioner” and may play a role in the observed prevalence of detrimental type-2 responses in melanoma. Several melanoma-associated antigens have been targeted in immunization strategies to treat melanoma patients. However, the therapeutic efficacy of these approaches remains limited, indicating an urgent need for improvement. Because MMP-2 activity is critical for melanoma progression, it represents an interesting target for vaccine therapy. We show that MMP-2 is an immunogenic tumor antigen. However, MMP-2-specific CD4+ T lymphocytes display a suboptimal inflammatory TH2 profile. MMP-2-conditoned DCs prime TH2 responses against several melanoma-associated antigen (MAA), suggesting that MMP-2 can create a TH2 skewing microenvironment in a bystander fashion. Elucidation of the underlying mechanisms opens the way to improving immune responses towards a more effective TH1 response, and highlights the potential of MMP2 as a target antigen in melanoma.
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I型Interferon自分泌 - 核酸环与树突状细胞的Toll样受体诱导的白介素-12p70分泌有关。
影响因子：
15.3
作者：
Gautier, G;Humbert, M;Deauvieau, F;Scuiller, M;Hiscott, J;Bates, EEM;Trinchieri, G;Caux, C;Garrone, P
通讯作者：
Garrone, P
影响因子：
15.3
作者：
Godefroy, E;Moreau-Aubry, A;Guilloux, Y
通讯作者：
Guilloux, Y
影响因子：
64.5
作者：
Brooks, PC;Stromblad, S;Cheresh, DA
通讯作者：
Cheresh, DA
DOI：
10.1084/jem.20051745
发表时间：
2006-02-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liu YJ
通讯作者：
Liu YJ
影响因子：
11.2
作者：
Minkis, Kira;Kavanagh, Daniel G.;Bhardwaj, Nina
通讯作者：
Bhardwaj, Nina