Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Russel H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS Biol. 2020 Feb 18;18(2):e3000590. doi: 10.1371/journal.pbio.3000590. eCollection 2020 Feb.
DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.
DO（人类中的 HLA-DO，小鼠中的 H2-O）是一种高度保守的非经典主要组织相容性复合体 II 类（MHC II）辅助分子，主要在胸腺髓质和 B 细胞中表达。先前的报告表明 DO 与自身免疫、丙型肝炎（HCV）感染和癌症之间可能存在关联，但 DO 如何导致这些疾病的机制尚不清楚。在这里，我们使用了一系列体内方法的组合，包括肽洗脱、混合淋巴细胞反应、T 细胞受体（TCR）深度测序、四聚体引导的幼稚 CD4 T 细胞前体计数和全身成像，报告了 DO 影响 B 细胞和胸腺上皮细胞呈递的自身肽库。DO 对表位呈递和胸腺选择产生不同的影响，从而改变 CD4 T 细胞前体频率。我们的发现通过证明缺乏 DO 会增加自身反应性和易感性，从而增加自身免疫性疾病的发展，在两种自身免疫性疾病模型中得到了验证。
