College of Life Sciences, Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang University, Hangzhou, China.
Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Front Immunol. 2018 May 31;9:1204. doi: 10.3389/fimmu.2018.01204. eCollection 2018.
CD58 and CD2 have long been known as a pair of reciprocal adhesion molecules involved in the immune modulations of CD8 T and NK-mediated cellular immunity in humans and several other mammals. However, the functional roles of CD58 and CD2 in CD4 T-mediated adaptive humoral immunity remain poorly defined. Moreover, the current functional observations of CD58 and CD2 were mainly acquired from assays, and investigation is greatly limited due to the absence of a homology in murine models. In this study, we identified and homologs from the model species zebrafish (). These two molecules share conserved structural features to their mammalian counterparts. Functionally, and were significantly upregulated on antigen-presenting cells and Cd4 T cells upon antigen stimulation. Blockade or knockdown of Cd58 and Cd2 dramatically impaired the activation of antigen-specific Cd4 T and mIgM B cells, followed by the inhibition of antibody production and host defense against bacterial infections. These results indicate that CD58/CD2 interaction was required for the full activation of CD4 T-mediated adaptive humoral immunity. The interaction of Cd58 with Cd2 was confirmed by co-immunoprecipitation and functional competitive assays by introducing a soluble Cd2 protein. This study highlights a new costimulatory mechanism underlying the regulatory network of adaptive immunity and makes zebrafish an attractive model organism for the investigation of CD58/CD2-mediated immunology and disorders. It also provides a cross-species understanding of the evolutionary history of costimulatory signals from fish to mammals as a whole.
CD58 和 CD2 长期以来一直被认为是一对相互作用的粘附分子，参与人类和其他几种哺乳动物的 CD8 T 和 NK 介导的细胞免疫的免疫调节。然而，CD58 和 CD2 在 CD4 T 介导的适应性体液免疫中的功能作用仍未得到明确界定。此外，由于在鼠模型中缺乏同源性，目前对 CD58 和 CD2 的功能观察主要来自于体外实验，体内研究受到极大限制。在这项研究中，我们从模式生物斑马鱼（Danio rerio）中鉴定出 CD58 和 CD2 的同源物（）。这两个分子与其哺乳动物对应物具有保守的结构特征。功能上，在抗原刺激下，抗原呈递细胞和 Cd4 T 细胞上的 Cd58 和 Cd2 显著上调。阻断或敲低 Cd58 和 Cd2 会显著损害抗原特异性 Cd4 T 和 mIgM B 细胞的激活，随后抑制抗体产生和宿主对细菌感染的防御。这些结果表明，CD58/CD2 相互作用是 CD4 T 介导的适应性体液免疫完全激活所必需的。通过共免疫沉淀和引入可溶性 Cd2 蛋白的功能竞争实验证实了 Cd58 与 Cd2 的相互作用。这项研究强调了适应性免疫调控网络中的一个新的共刺激机制，并使斑马鱼成为研究 CD58/CD2 介导的免疫学和疾病的有吸引力的模式生物。它还提供了一个跨物种的理解，从鱼类到哺乳动物的共刺激信号的进化历史。
