Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia.
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia.
J Biol Chem. 2020 Mar 6;295(10):3239-3246. doi: 10.1074/jbc.RA119.010509. Epub 2020 Jan 28.
The immune co-receptor CD8 molecule (CD8) has two subunits, CD8α and CD8β, which can assemble into homo or heterodimers. Nonclassical (class-Ib) major histocompatibility complex (MHC) molecules (MHC-Ibs) have recently been identified as ligands for the CD8αα homodimer. This was demonstrated by the observation that histocompatibility 2, Q region locus 10 (H2-Q10) is a high-affinity ligand for CD8αα which also binds the MHC-Ib molecule H2-TL. This suggests that MHC-Ib proteins may be an extended source of CD8αα ligands. Expression of H2-T3/TL and H2-Q10 is restricted to the small intestine and liver, respectively, yet CD8αα-containing lymphocytes are present more broadly. Therefore, here we sought to determine whether murine CD8αα binds only to tissue-specific MHC-Ib molecules or also to ubiquitously expressed MHC-Ib molecules. Using recombinant proteins and surface plasmon resonance-based binding assays, we show that the MHC-Ib family furnishes multiple binding partners for murine CD8αα, including H2-T22 and the CD94/NKG2-A/B-activating NK receptor (NKG2) ligand Qa-1 We also demonstrate a hierarchy among MHC-Ib proteins with respect to CD8αα binding, in which Qa-1 > H2-Q10 > TL. Finally, we provide evidence that Qa-1 is a functional ligand for CD8αα, distinguishing it from its human homologue MHC class I antigen E (HLA-E). These findings provide additional clues as to how CD8αα-expressing cells are controlled in different tissues. They also highlight an unexpected immunological divergence of Qa-1/HLA-E function, indicating the need for more robust studies of murine MHC-Ib proteins as models for human disease.
免疫共受体 CD8 分子（CD8）由两个亚基，CD8α 和 CD8β 组成，可以组装成同型或异型二聚体。非经典（I 类）主要组织相容性复合体（MHC）分子（MHC-Ibs）最近被鉴定为 CD8αα 同型二聚体的配体。这是通过观察到组织相容性 2、Q 区基因座 10（H2-Q10）是 CD8αα 的高亲和力配体，也与 MHC-Ib 分子 H2-TL 结合而证明的。这表明 MHC-Ib 蛋白可能是 CD8αα 配体的扩展来源。H2-T3/TL 和 H2-Q10 的表达分别局限于小肠和肝脏，而含有 CD8αα 的淋巴细胞则更为广泛存在。因此，在这里我们试图确定小鼠 CD8αα 是否仅与组织特异性 MHC-Ib 分子结合，还是也与广泛表达的 MHC-Ib 分子结合。使用重组蛋白和基于表面等离子体共振的结合测定法，我们表明 MHC-Ib 家族为小鼠 CD8αα 提供了多种结合伴侣，包括 H2-T22 和 CD94/NKG2-A/B 激活 NK 受体（NKG2）配体 Qa-1。我们还证明了 MHC-Ib 蛋白在与 CD8αα 结合方面存在层次结构，其中 Qa-1＞H2-Q10＞TL。最后，我们提供了证据表明 Qa-1 是 CD8αα 的功能性配体，将其与人类同源物 MHC 类 I 抗原 E（HLA-E）区分开来。这些发现为 CD8αα 表达细胞在不同组织中如何受到控制提供了更多线索。它们还突出了 Qa-1/HLA-E 功能的意外免疫差异，表明需要更深入地研究小鼠 MHC-Ib 蛋白作为人类疾病模型。
