Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression.
Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression.
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DOI：
10.1186/s12977-014-0116-6
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发表时间：
2014-12-14
期刊：
影响因子：
3.3
通讯作者：
Bangham CR
中科院分区：
文献类型：
--
作者：
Rowan AG;Suemori K;Fujiwara H;Yasukawa M;Tanaka Y;Taylor GP;Bangham CR
免疫遗传学证据表明，针对弱CTL抗原HBZ特异性的细胞毒性T淋巴细胞（CTL）在体内限制HTLV-1的前病毒载量，而前病毒载量与免疫优势抗原Tax特异性CTL的频率之间没有明确的关系。在体内，循环htlv -1感染的细胞表达HBZ mRNA，而Tax的表达通常很低或检测不到。为了阐明靶向HBZ的CTL的病毒抑制潜力，我们通过将HBZ和tax特异性CTL克隆与来自hla匹配的htlv -1感染供者的原代CD4+ T细胞共孵育，比较了HBZ和tax特异性CTL裂解自然感染细胞的能力。我们量化了感染细胞的裂解，并测试了特异性病毒诱导的宿主细胞表面分子是否决定了感染细胞对ctl介导的裂解的易感性。原代感染细胞在表达Tax的同时上调HLA-A*02、ICAM-1、Fas和TRAIL-R1/2，形成htlv -1特异性ctl和不相关病毒特异性ctl的有效靶标。我们检测了HBZ mRNA（剪接异构体）在表达tax和不表达tax的感染细胞中的表达，HBZ26-34表位被转染HBZ表达质粒的细胞加工和呈递。然而，当与原代细胞共孵育时，高亲和性hbz特异性CTL克隆杀死的感染细胞明显少于税收特异性CTL克隆杀死的感染细胞。最后，与Tax-或hbz特异性ctl孵育可显著降低表达高水平HLA-A*02的细胞频率。HTLV-1基因在原代CD4+ T细胞中的表达非特异性地增加对CTL裂解的易感性。尽管存在HBZ剪接异构体mRNA，但原代细胞的HBZ表位呈递效率明显低于Tax。本文的在线版本（doi:10.1186/s12977-014- 016 -6）包含补充材料，可供授权用户使用。
Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ- and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ- and Tax-specific CTL clones with primary CD4+ T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis. Primary infected cells upregulated HLA-A*02, ICAM-1, Fas and TRAIL-R1/2 in concert with Tax expression, forming efficient targets for both HTLV-1-specific CTLs and CTLs specific for an unrelated virus. We detected expression of HBZ mRNA (spliced isoform) in both Tax-expressing and non-expressing infected cells, and the HBZ26–34 epitope was processed and presented by cells transfected with an HBZ expression plasmid. However, when coincubated with primary cells, a high-avidity HBZ-specific CTL clone killed significantly fewer infected cells than were killed by a Tax-specific CTL clone. Finally, incubation with Tax- or HBZ-specific CTLs resulted in a significant decrease in the frequency of cells expressing high levels of HLA-A*02. HTLV-1 gene expression in primary CD4+ T cells non-specifically increases susceptibility to CTL lysis. Despite the presence of HBZ spliced-isoform mRNA, HBZ epitope presentation by primary cells is significantly less efficient than that of Tax. The online version of this article (doi:10.1186/s12977-014-0116-6) contains supplementary material, which is available to authorized users.
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