Suzuki Hiromu, Kunimatsu Yuka, Yoshioka Yuya, Asa Minori, Yamasaki Sho, Sugita Masahiko, Morita Daisuke
Laboratory of Cell Regulation, Department of Virus Research, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Laboratory of Cell Regulation and Molecular Network, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
J Immunol. 2025 Jul 1;214(7):1483-1492. doi: 10.1093/jimmun/vkaf082.
A novel subset of classical major histocompatibility complex class I molecules has recently been identified in rhesus monkeys that mediates the presentation of N-myristoylated lipopeptides, rather than conventional peptides, to CD8+ cytotoxic T lymphocytes (CTLs). For example, the rhesus Mamu-B098 allomorph binds an N-terminal 5-mer fragment (C14 fatty acid-Gly-Gly-Ala-Ile-Ser; C14nef5) derived from the N-myristoylated SIV Nef protein and activates C14nef5-specific CTLs. Additionally, a transporter for antigen presentation (TAP)-independent cell-surface expression was observed for Mamu-B098 in the in vitro transfection experiments, leading us to hypothesize that TAP-independent pathways may exist for CTL activation. To address this directly, we generated transgenic mice expressing Mamu-B098 and analyzed its function under TAP-deficient conditions. We first confirmed that its expression level was unchanged on the surface of TAP-deficient cells compared with that of TAP-sufficient cells. Second, the CD8+ T cell population, but not the CD4+ T cell population, increased in TAP knockout (KO) mice as a result of the acquisition of Mamu-B098 expression. Third, C14nef5-specific, Mamu-B098-restricted CD8+ T cells were readily inducible in Mamu-B098 transgenic/TAP KO but not in nontransgenic/TAP KO mice. Finally, the CD8+ T cells expressed cytolytic granule contents and functioned as CTLs. These findings provide evidence that in addition to conventional peptide-specific CTL responses that require TAP, an alternative TAP-independent pathway for CTL activation exists in primates. This novel pathway may be valuable when TAP is targeted by pathogenic viruses for immune evasion. We propose that the established concept of major histocompatibility complex class I biology may require modifications to incorporate TAP-independent pathways of lipopeptide-specific CTL responses.
最近在恒河猴中发现了一类新的经典主要组织相容性复合体I类分子，它介导将N-肉豆蔻酰化脂肽而非传统肽呈递给CD8+细胞毒性T淋巴细胞（CTL）。例如，恒河猴Mamu-B098同种异型分子结合源自N-肉豆蔻酰化的SIV Nef蛋白的N端5聚体片段（C14脂肪酸-甘氨酸-甘氨酸-丙氨酸-异亮氨酸-丝氨酸；C14nef5），并激活C14nef5特异性CTL。此外，在体外转染实验中观察到Mamu-B098在不依赖抗原呈递转运体（TAP）的情况下在细胞表面表达，这使我们推测可能存在不依赖TAP的CTL激活途径。为了直接解决这个问题，我们构建了表达Mamu-B098的转基因小鼠，并分析了其在TAP缺陷条件下的功能。我们首先证实，与TAP充足的细胞相比，其在TAP缺陷细胞表面的表达水平没有变化。其次，由于获得了Mamu-B098的表达，TAP基因敲除（KO）小鼠中的CD8+ T细胞群体增加，而CD4+ T细胞群体没有增加。第三，在Mamu-B098转基因/TAP KO小鼠中很容易诱导出C14nef5特异性、Mamu-B098限制性的CD8+ T细胞，而在非转基因/TAP KO小鼠中则不能。最后，CD8+ T细胞表达溶细胞颗粒成分并发挥CTL的功能。这些发现提供了证据，表明除了需要TAP的传统肽特异性CTL反应外，灵长类动物中还存在一种不依赖TAP的CTL激活替代途径。当致病性病毒靶向TAP进行免疫逃避时，这种新途径可能很有价值。我们建议，主要组织相容性复合体I类生物学的既定概念可能需要修改，以纳入脂肽特异性CTL反应的不依赖TAP途径。
