近日，荷兰阿姆斯特丹大学Robbert M. Spaapen及其小组发现，鞘糖脂调控HLA-I介导的免疫反应。相关论文于2020年12月2日在线发表在《免疫》杂志上。
由于恢复HLA-1抗原呈递的选择有限，因此研究人员旨在确定可药物治疗的HLA-1途径靶标。使用全基因组的迭代筛选，研究人员发现细胞表面鞘糖脂（GSL）库决定了有效的HLA-1抗原呈递。研究人员表明，蛋白酶SPPL3的缺乏增强了B3GNT5酶的活性，导致表面GSL的上调。这些GSL在空间上阻碍了抗体和受体与HLA-1的相互作用，并减少了CD8+T细胞的活化。此外，神经胶质瘤中SPPL3-B3GNT5途径受阻与患者生存率降低相关。
研究人员表明，使用临床批准的药物可以通过抑制GSL合成来逆转免疫调节作用。总体而言，这项研究确定了GSL的特征，这些特征可抑制免疫识别并且是癌症、感染和自身免疫的潜在治疗靶标。
据介绍，HLA-1糖蛋白通过将抗原呈递给相关的CD8+T细胞来驱动免疫应答。此过程通常被肿瘤和病原体劫持以逃避免疫。
附：英文原文
Title: The SPPL3-Defined Glycosphingolipid Repertoire Orchestrates HLA Class I-Mediated Immune Responses
Author: Marlieke L.M. Jongsma, Antonius A. de Waard, Matthijs Raaben, Tao Zhang, Birol Cabukusta, René Platzer, Vincent A. Blomen, Anastasia Xagara, Tamara Verkerk, Sophie Bliss, Xiangrui Kong, Carolin Gerke, Lennert Janssen, Elmer Stickel, Stephanie Holst, Rosina Plomp, Arend Mulder, Soldano Ferrone, Frans H.J. Claas, Mirjam H.M. Heemskerk, Marieke Griffioen, Anne Halenius, Hermen Overkleeft, Johannes B. Huppa, Manfred Wuhrer, Thijn R. Brummelkamp, Jacques Neefjes, Robbert M. Spaapen
Issue&Volume: 2020-12-02
Abstract: HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens tocognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion.Because options for restoring HLA-I antigen presentation are limited, we aimed toidentify druggable HLA-I pathway targets. Using iterative genome-wide screens, weuncovered that the cell surface glycosphingolipid (GSL) repertoire determines effectiveHLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5enzyme activity, resulting in upregulation of surface neolacto-series GSLs. TheseGSLs sterically impeded antibody and receptor interactions with HLA-I and diminishedCD8+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlatedwith decreased patient survival. We show that the immunomodulatory effect could bereversed through GSL synthesis inhibition using clinically approved drugs. Overall,our study identifies a GSL signature that inhibits immune recognition and representsa potential therapeutic target in cancer, infection, and autoimmunity.
DOI: 10.1016/j.immuni.2020.11.003
Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30468-4
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本期文章：《免疫》：Online/在线发表
