CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis.
CADM1/TSLC1 Identifies HTLV-1-Infected Cells and Determines Their Susceptibility to CTL-Mediated Lysis.
复制标题
DOI：
10.1371/journal.ppat.1005560
复制
发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Bangham CR
中科院分区：
文献类型：
--
作者：
Manivannan K;Rowan AG;Tanaka Y;Taylor GP;Bangham CR
人类T细胞嗜淋巴细胞病毒-1（HTLV-1）主要感染CD 4 + T细胞，在5%至10%的携带者中引起炎症性疾病或T细胞恶性肿瘤。细胞毒性T淋巴细胞（CTL）反应是控制病毒载量和疾病风险的关键因素。在原代细胞中检测病毒蛋白Tax的能力使得有可能估计持续感染者中表达Tax的感染细胞被CTL消除的速率。然而，大多数HTLV-1感染的细胞在给定的时间是Tax-，并且它们的免疫表型很难定义。在这里，我们的目的是确定由Tax+和Tax-HTLV-1感染的细胞表达的细胞表面分子，并使用它来分析新鲜外周血单核细胞中的CTL应答。细胞粘附分子1（CADM 1/TSLC 1）是HTLV-1感染的最佳单一标志物，其识别HTLV-1感染细胞的灵敏度和特异性高于CD 25、CCR 4或ICAM-1。CADM 1 + CD 4 + T细胞在外周血中携带65%的前病毒拷贝的中位数。在一个23人的队列中，我们量化了CTL介导的Tax+和Tax-CADM 1+细胞的杀伤率。我们表明，CADM 1的表达与感染细胞对CTL裂解的敏感性增强有关：尽管Tax在CTL应答中具有免疫优势，但Tax+ CADM 1-细胞不能有效地被CTL裂解。CD 8 + T细胞上CADM 1配体CRTAM的上调与感染细胞的有效裂解相关。Tax-CADM 1+细胞被自体CTL以非常低的速率裂解，然而，当加载外源肽抗原时，被有效地杀死。面对增强的CTL反选择，大多数HTLV-1感染的细胞上CADM 1的高表达意味着CADM 1赋予病毒强大的益处。人T细胞嗜淋巴细胞病毒-1（HTLV-1）在宿主的一生中感染白色血细胞（CD 4 + T细胞）。免疫反应限制了病毒的传播，免疫反应弱的人患侵袭性血癌或涉及不可逆脊髓损伤的疾病的风险很高。病毒和宿主进行着一场持续的战斗：病毒蛋白驱动宿主细胞分裂或感染新的细胞。我们知道病毒蛋白Tax是免疫反应的重要靶点，产生Tax的细胞很快就会被杀死。不产生Tax的感染细胞很难检测到，所以我们不知道它们被杀死的速度有多快。在本文中，我们表明，大多数感染细胞的表面上有一个宿主蛋白“CADM 1”。我们测量了CADM 1细胞的杀伤，发现Tax+ CADM 1+细胞是唯一被免疫应答强烈靶向的感染细胞。我们还发现，表面没有CADM 1的感染细胞逃脱了杀伤，这表明CADM 1有助于HTLV-1的免疫控制。这些发现是我们理解慢性感染中细胞更新和免疫控制的重要一步。
Human T cell lymphotropic virus-1 (HTLV-1) primarily infects CD4+ T cells, causing inflammatory disorders or a T cell malignancy in 5% to 10% of carriers. The cytotoxic T lymphocyte (CTL) response is a key factor that controls the viral load and thus the risk of disease. The ability to detect the viral protein Tax in primary cells has made it possible to estimate the rate at which Tax-expressing infected cells are eliminated by CTLs in persistently infected people. However, most HTLV-1-infected cells are Tax–at a given time, and their immunophenotype is poorly defined. Here, we aimed to identify a cell-surface molecule expressed by both Tax+ and Tax–HTLV-1-infected cells and use it to analyse the CTL response in fresh peripheral blood mononuclear cells. Cell adhesion molecule 1 (CADM1/TSLC1) was the best single marker of HTLV-1 infection, identifying HTLV-1-infected cells with greater sensitivity and specificity than CD25, CCR4 or ICAM-1. CADM1+CD4+ T cells carried a median of 65% of proviral copies in peripheral blood. In a cohort of 23 individuals, we quantified the rate of CTL-mediated killing of Tax+ and Tax−CADM1+ cells. We show that CADM1 expression is associated with enhanced susceptibility of infected cells to CTL lysis: despite the immunodominance of Tax in the CTL response, Tax+CADM1– cells were inefficiently lysed by CTLs. Upregulation of the CADM1 ligand CRTAM on CD8+ T cells correlated with efficient lysis of infected cells. Tax–CADM1+ cells were lysed at a very low rate by autologous CTLs, however, were efficiently killed when loaded with exogenous peptide antigen. High expression of CADM1 on most HTLV-1-infected cells in the face of enhanced CTL counterselection implies that CADM1 confers a strong benefit on the virus. Human T cell lymphotropic virus-1 (HTLV-1) infects white blood cells (CD4+ T cells) for the lifetime of the host. The immune response limits viral spread, and people with a weak immune response have a high risk of developing an aggressive blood cancer, or a condition involving irreversible spinal cord damage. Virus and host are engaged in a constant battle: virus proteins drive the host cell to divide or infect new cells. We know that the viral protein Tax is an important target of the immune response, and cells which produce Tax are killed quickly. Infected cells which do not produce Tax are difficult to detect, so we have no idea how quickly they are killed. In this paper we show that most infected cells have a host protein ‘CADM1’ on their surface. We measured killing of CADM1 cells and saw that Tax+CADM1+ cells are the only infected cells which are strongly targeted by the immune response. We also found that infected cells which did not have CADM1 on the surface escaped killing, showing that CADM1 aids in immune control of HTLV-1. These findings are an important step forward in our understanding of cellular turnover and immune control in chronic infection.