Association of Marek's Disease induced immunosuppression with activation of a novel regulatory T cells in chickens.
Association of Marek's Disease induced immunosuppression with activation of a novel regulatory T cells in chickens.
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DOI：
10.1371/journal.ppat.1006745
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发表时间：
2017-12
期刊：
影响因子：
6.7
通讯作者：
Behboudi S
中科院分区：
文献类型：
--
作者：
Gurung A;Kamble N;Kaufer BB;Pathan A;Behboudi S
马立克氏病病毒（MDV）是一种α疱疹病毒，感染鸡，转化CD 4 + T细胞，并导致致命的淋巴瘤。此外，MDV通过诱导受感染淋巴细胞的细胞死亡并且可能由于调节性T（Treg）细胞的活化而在感染期间早期诱导免疫抑制。此外，免疫抑制也发生在疾病的转化阶段;然而，仍然不知道该疾病如何在淋巴瘤形成之前或之后抑制免疫应答。在这里，我们证明了鸡TGF-β + Treg细胞存在于不同的淋巴组织中，在肠道相关淋巴组织（盲肠扁桃体：CT）中发现的水平最高，促进了TGF-β发挥的免疫特权微环境。令人惊讶的是，与抗性品系相比，在MDV易感鸡品系的脾脏中发现显著更高频率的TGF-β + Treg细胞，表明TGF-β + Treg细胞与宿主对淋巴瘤形成的易感性之间存在关联。实验性感染强毒MDV后，肺中TGF-β + Treg细胞的水平早在感染后4天就升高了，并且在脾脏中的疾病转化期期间升高了。与TGF-β + Treg细胞相反，CD 4 + CD 25 + T细胞的水平在疾病的感染和转化阶段保持不变。此外，我们的结果表明TGF-β + Treg细胞的诱导与疾病的发病机制相关，因为MDV疫苗株不诱导TGF-β + Treg细胞。与人类造血恶性细胞类似，MDV诱导的淋巴瘤细胞表达高水平的TGF-β，但表达极低水平的TGF-β受体I和II基因。结果证实考克斯-2/PGE 2通路参与MDV-淋巴瘤细胞诱导的免疫抑制。综上所述，我们的结果揭示了鸡中一种新的TGF-β + Treg亚群，该亚群在MDV感染和肿瘤形成期间被激活。Treg细胞对于维持耐受性和控制免疫反应至关重要，特别是在病毒感染和肿瘤形成期间。马立克氏病病毒（MDV）感染引起鸡的免疫抑制并诱导CD 4 + T细胞转化。在这里，我们证明了一群鸡CD 4 + T细胞表达抑制分子，包括TGF-β，并具有免疫调节特性。在不同的鸡淋巴组织中检测到TGF-β + Treg细胞，在盲肠扁桃体中检测到的最高。对MDV诱导的淋巴瘤形成易感的鸡品系与MDV抗性鸡品系相比具有更高的TGF-β + Treg细胞频率。用强毒MDV感染鸡增加了TGF-β + Treg细胞的数量，这在用MDV疫苗株感染后没有改变。MDV转化的CD 4 + T细胞产生高水平的TGF-β，而与非转化的CD 4 + T细胞相比，它们表达非常低水平的TGF-β受体。此外，MDV诱导的淋巴瘤细胞表达可抑制T细胞功能的可溶性抑制因子;然而，这些可溶性因子不能抑制淋巴瘤细胞的增殖。我们首次鉴定了鸡TGF-β + Treg细胞，并证明这些细胞参与MDV感染的发病机制和免疫抑制。
Marek’s Disease Virus (MDV) is an alphaherpesvirus that infects chickens, transforms CD4+ T cells and causes deadly lymphomas. In addition, MDV induces immunosuppression early during infection by inducing cell death of the infected lymphocytes, and potentially due to activation of regulatory T (Treg)-cells. Furthermore, immunosuppression also occurs during the transformation phase of the disease; however, it is still unknown how the disease can suppress immune response prior or after lymphoma formation. Here, we demonstrated that chicken TGF-beta+ Treg cells are found in different lymphoid tissues, with the highest levels found in the gut-associated lymphoid tissue (cecal tonsil: CT), fostering an immune-privileged microenvironment exerted by TGF-beta. Surprisingly, significantly higher frequencies of TGF-beta+ Treg cells are found in the spleens of MDV-susceptible chicken lines compared to the resistant line, suggesting an association between TGF-beta+ Treg cells and host susceptibility to lymphoma formation. Experimental infection with a virulent MDV elevated the levels of TGF-beta+ Treg cells in the lungs as early as 4 days post infection, and during the transformation phase of the disease in the spleens. In contrast to TGF-beta+ Treg cells, the levels of CD4+CD25+ T cells remained unchanged during the infection and transformation phase of the disease. Furthermore, our results demonstrate that the induction of TGF-beta+ Treg cells is associated with pathogenesis of the disease, as the vaccine strain of MDV did not induce TGF-beta+ Treg cells. Similar to human haematopoietic malignant cells, MDV-induced lymphoma cells expressed high levels of TGF-beta but very low levels of TGF-beta receptor I and II genes. The results confirm that COX-2/ PGE2 pathway is involved in immunosuppression induced by MDV-lymphoma cells. Taken together, our results revealed a novel TGF-beta+ Treg subset in chickens that is activated during MDV infection and tumour formation. Treg cells are crucial for the maintenance of tolerance and control of immune responses, especially during viral infection and tumour formation. Marek’s Disease Virus (MDV) infection causes immunosuppression and induces transformation of CD4+ T cells in chicken. Here we demonstrate that a population of chicken CD4+ T cells express inhibitory molecules including TGF-beta and have immune-regulatory properties. TGF-beta+ Treg cells are detected in different chicken lymphoid tissues, the highest being detected in cecal tonsils. Chicken lines susceptible to MDV-induced lymphoma formation have higher frequencies of TGF-beta+ Treg cells compared to the MDV resistant chicken line. Infection of chicken with a virulent MDV increased the numbers of TGF-beta+ Treg cells, which was not changed after infection with the MDV vaccine strain. MDV-transformed CD4+ T cells produce high levels of TGF-beta, while they express very low levels of TGF-beta receptors compared to non-transformed CD4+ T cells. In addition, MDV-induced lymphoma cells express soluble suppressive factors that can inhibit T cell function; however these soluble factors cannot suppress proliferation of the lymphoma cells. For the first time, we identified chicken TGF-beta+ Treg cells and demonstrate that these cells are involved in pathogenesis and immunosuppression of MDV infection.
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影响因子：
12.8
作者：
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影响因子：
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1α，25（OH）2维生素D3调节鸟类T淋巴细胞功能，而不会引起CTL无反应性。
影响因子：
3.7
作者：
Boodhoo N;Sharif S;Behboudi S
通讯作者：
Behboudi S