Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28232-28238. doi: 10.1073/pnas.2013554117. Epub 2020 Oct 23.
Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans ( = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.
人类白细胞抗原（HLA）I 类同种异型在缺乏肽加载复合物的必需组成部分 tapasin 的情况下呈现肽的能力有所不同。我们量化了在欧洲裔和非裔美国人中常见的所有同种异型的 tapasin 依赖性（n = 97），结果显示出广泛的连续谱。对感染个体的整个 HIV-1 蛋白质组的细胞毒性 T 细胞反应的体外检测表明，tapasin 依赖性同种异型比 tapasin 非依赖性同种异型呈现更有限的一组独特肽，这一数据得到了计算预测的支持。这表明，tapasin 依赖性的变化可能通过改变肽库大小来影响免疫反应的强度。为了支持这一模型，我们观察到，携带 tapasin 独立性更大的 基因型的个体进展到艾滋病的速度较慢，病毒载量较低，这可能是由于肽呈递的广度增加所致。因此，tapasin 依赖性水平，就像 基因型一样，可能成为限制或扩大人类 HLA-I 肽库广度的一种手段，最终影响对病原体和疫苗的免疫反应。
