美国费城儿童医院Laurence C. Eisenlohr研究小组在研究中取得进展。他们的研究显示流感隐性主要组织相容性复合体 （MHC）-E表位能诱导有效的细胞溶解性T细胞反应。该项研究成果发表在2023年10月12日出版的《自然-免疫学》上。

研究人员使用免疫肽疗法来寻找非典型表位，这些表位诱导感染流感病毒A/Puerto Rico/8/1934小鼠的T细胞反应。研究人员发现了一个含有九个氨基酸的表位，称为M-SL9，它诱导显性共免疫，其细胞溶解性CD8 T细胞反应在以下两个方面是非常规的：首先，它由Qa-1呈现；其次，它具有神秘的来源，其由流感基质基因片段的未注释替代阅读框编码。M-SL9的呈递和免疫原性取决于正义链RNA片段的第二个AUG密码子，这提示其通过渗漏核糖体扫描启动翻译。在流感病毒A/Puerto Rico/8/1934感染期间，M-SL9特异性T细胞很少从肺部排出并大量分化为组织驻留记忆细胞。

重要的是，研究表明信使RNA疫苗接种能大量诱导M-SL9/Qa-1特异性T细胞，并且可以介导体内抗原特异性细胞溶解。该研究结果表明，非典型翻译产物占据T细胞库的重要部分，并且越来越多的证据表明MHC-E限制性T细胞可能具有实质的治疗价值。

据介绍，在多大程度上非典型抗原呈递诱导T细胞免疫的机制尚不清楚。一般，CD8 T细胞可识别与典型主要组织相容性复合体 I 类或MHC-Ia相关的病毒肽或表位，但在某些情况下，免疫监视可以针对非经典MHC-Ib呈递的肽，特别是MHC-E蛋白（小鼠中Qa-1和人类HLA-E）;然而，尚不清楚非经典反应在抗病毒免疫中的重要性。同样不确定的是“神秘”病毒表位的重要性，因为传统映射技术无法检测到其存在。

附：英文原文

Title: Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response

Author: Hogan, Michael J., Maheshwari, Nikita, Begg, Bridget E., Nicastri, Annalisa, Hedgepeth, Emma J., Muramatsu, Hiromi, Pardi, Norbert, Miller, Michael A., Reilly, Shanelle P., Brossay, Laurent, Lynch, Kristen W., Ternette, Nicola, Eisenlohr, Laurence C.

Issue&Volume: 2023-10-12

Abstract: The extent to which unconventional forms of antigen presentation drive T cell immunity is unknown. By convention, CD8 T cells recognize viral peptides, or epitopes, in association with classical major histocompatibility complex (MHC) class I, or MHC-Ia, but immune surveillance can, in some cases, be directed against peptides presented by nonclassical MHC-Ib, in particular the MHC-E proteins (Qa-1 in mice and HLA-E in humans); however, the overall importance of nonclassical responses in antiviral immunity remains unclear. Similarly uncertain is the importance of ‘cryptic’ viral epitopes, defined as those undetectable by conventional mapping techniques. Here we used an immunopeptidomic approach to search for unconventional epitopes that drive T cell responses in mice infected with influenza virus A/Puerto Rico/8/1934. We identified a nine amino acid epitope, termed M-SL9, that drives a co-immunodominant, cytolytic CD8 T cell response that is unconventional in two major ways: first, it is presented by Qa-1, and second, it has a cryptic origin, mapping to an unannotated alternative reading frame product of the influenza matrix gene segment. Presentation and immunogenicity of M-SL9 are dependent on the second AUG codon of the positive sense matrix RNA segment, suggesting translation initiation by leaky ribosomal scanning. During influenza virus A/Puerto Rico/8/1934 infection, M-SL9-specific T cells exhibit a low level of egress from the lungs and strong differentiation into tissue-resident memory cells. Importantly, we show that M-SL9/Qa-1-specific T cells can be strongly induced by messenger RNA vaccination and that they can mediate antigen-specific cytolysis in vivo. Our results demonstrate that noncanonical translation products can account for an important fraction of the T cell repertoire and add to a growing body of evidence that MHC-E-restricted T cells could have substantial therapeutic value.

DOI: 10.1038/s41590-023-01644-5

Source: https://www.nature.com/articles/s41590-023-01644-5