Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection.
Neddylation contributes to CD4+ T cell-mediated protective immunity against blood-stage Plasmodium infection.
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Neddylation 有助于 CD4 T 细胞介导的针对血液阶段疟原虫感染的保护性免疫。
DOI：
10.1371/journal.ppat.1007440
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发表时间：
2018-11
期刊：
影响因子：
6.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Cheng Q;Liu J;Pei Y;Zhang Y;Zhou D;Pan W;Zhang J
CD 4 + T细胞在针对血液期疟原虫感染的保护性免疫中起主要作用，既用于IFN-γ依赖性效应器机制，又提供B细胞辅助信号。Neddylation是一种由NEDD 8与特定靶点共价结合引发的泛素化样过程，已成为T细胞活性与TCR结合的潜在调节因子。然而，其对T细胞介导的对血液期疟疾的免疫的贡献仍不清楚。在这里，使用约氏疟原虫17 XNL诱导的实验模型，和条件性基因敲除小鼠与T细胞特异性缺陷的neddylation途径的关键组成部分，我们证明了在血液阶段疟原虫感染期间T细胞中的neddylation的激活对于寄生虫控制和宿主存活是必不可少的。从机制上讲，我们表明，除了促进CD 4 + T细胞活化，增殖和保护性T辅助1（Th 1）细胞反应的发展，如前所述，neddylation也需要支持CD 4 + T细胞的生存，主要是通过B细胞淋巴瘤-2（Bcl-2）介导的抑制细胞凋亡。此外，我们提供的证据表明，neddylation有助于滤泡辅助T（Tfh）细胞分化，可能通过增加泛素连接酶Itch活性和FoxO 1的蛋白酶体降解，从而促进生发中心（GC）的形成和寄生虫特异性抗体的产生。这项研究确定neddylation作为抗疟原虫免疫的正调节因子，并提供了深入了解这种途径参与宿主对感染性疾病的抵抗。由细胞内寄生虫疟原虫（Plasmodium）引起的疟疾仍然是每年具有显著发病率和死亡率的主要传染病。更好地了解对致病性血液阶段疟原虫的保护性免疫所涉及的分子机制将有助于抗疟疾药物和疫苗的开发。Neddylation最近被鉴定为T细胞功能的潜在调节剂。在这里，我们直接解决了neddylation对T细胞应答的影响和血液阶段约氏疟原虫17 XNL疟疾的结果。我们发现，T细胞中neddylation的激活对于IFN-γ介导的促炎反应和寄生虫特异性抗体的产生是必不可少的，从而有助于感染的完全解决。这主要与报道的neddylation对CD 4 + T细胞活性的有益作用有关，包括活化、增殖和分化为T辅助1（Th 1）细胞。此外，我们建立了neddylation在寄生虫反应性CD 4 + T细胞存活和滤泡辅助性T（Tfh）细胞分化中的新作用。因此，我们提供的证据表明，neddylation可能是一种新的机制，在协调最佳的CD 4 + T细胞效应反应和随后的体液免疫血液阶段疟原虫感染。
CD4+ T cells play predominant roles in protective immunity against blood-stage Plasmodium infection, both for IFN-γ-dependent effector mechanisms and providing B cell helper signals. Neddylation, an ubiquitination-like process triggered by covalent conjugation of NEDD8 to specific targets, has emerged as a potential regulator of T cell activities to TCR engagement. However, its contribution to T cell-mediated immunity to blood-stage malaria remains unclear. Here using an experimental model induced by Plasmodium yoelii 17XNL, and conditional knockout mice with T cell-specific deficiency of crucial components of neddylation pathway, we demonstrate activation of neddylation in T cells during blood-stage Plasmodium infection is essential for parasite control and host survival. Mechanistically, we show that apart from promoting CD4+ T cell activation, proliferation, and development of protective T helper 1 (Th1) cell response as suggested previously, neddylation is also required for supporting CD4+ T cell survival, mainly through B-cell lymphoma-2 (Bcl-2) mediated suppression of the mitochondria-dependent apoptosis. Furthermore, we provide evidence that neddylation contributes to follicular helper T (Tfh) cell differentiation, probably via augmenting the ubiquitin ligase Itch activity and proteasomal degradation of FoxO1, thereby facilitating germinal center (GC) formation and parasite-specific antibody production. This study identifies neddylation as a positive regulator of anti-Plasmodium immunity and provides insight into an involvement of such pathway in host resistance to infectious diseases. Malaria, which is caused by the intracellular parasite Plasmodium, remains a major infectious disease with significant morbidity and mortality annually. Better understanding of the molecular mechanisms involved in protective immunity against the pathogenic blood-stage Plasmodium will facilitate development of anti-malarial drugs and vaccines. Neddylation has recently been identified as a potential regulator of T cell function. Here, we directly addressed the effects of neddylation on T cell responses and the outcome of blood-stage P. yoelii 17XNL malaria. We show that activation of neddylation in T cells is essential for IFN-γ-mediated proinflammatory response and generation of parasite-specific antibodies, thus contributing to full resolution of the infection. This is primarily associated with the reported beneficial effects of neddylation on CD4+ T cell activities, including activation, proliferation, and differentiation into T helper 1 (Th1) cells. Additionally, we establish a novel role of neddylation in parasite-responsive CD4+ T cell survival and follicular helper T (Tfh) cell differentiation. Therefore, we provide evidence that neddylation may represent a novel mechanism in orchestrating optimum CD4+ T cell effector response and subsequent humoral immunity to blood-stage Plasmodium infection.
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DOI：
10.1084/jem.20120219
发表时间：
2012-09-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liu X;Yan X;Zhong B;Nurieva RI;Wang A;Wang X;Martin-Orozco N;Wang Y;Chang SH;Esplugues E;Flavell RA;Tian Q;Dong C
通讯作者：
Dong C
影响因子：
16
作者：
Brownell, James E.;Sintchak, Michael D.;Dick, Lawrence R.
通讯作者：
Dick, Lawrence R.
影响因子：
10.5
作者：
Hochstrasser, M
通讯作者：
Hochstrasser, M
影响因子：
5.4
作者：
Alp, Oezen Sercan;Durlanik, Sibel;Schulz, Daniel;McGrath, Mairi;Gruen, Joachim R.;Bardua, Marcus;Ikuta, Koichi;Sgouroudis, Evridiki;Riedel, Rene;Zehentmeier, Sandra;Hauser, Anja E.;Tsuneto, Motokazu;Melchers, Fritz;Tokoyoda, Koji;Chang, Hyun-Dong;Thiel, Andreas;Radbruch, Andreas
通讯作者：
Radbruch, Andreas
影响因子：
6.7
作者：
Couper KN;Blount DG;Wilson MS;Hafalla JC;Belkaid Y;Kamanaka M;Flavell RA;de Souza JB;Riley EM
通讯作者：
Riley EM