CD86 Is a Selective CD28 Ligand Supporting FoxP3+ Regulatory T Cell Homeostasis in the Presence of High Levels of CTLA-4.
CD86 Is a Selective CD28 Ligand Supporting FoxP3+ Regulatory T Cell Homeostasis in the Presence of High Levels of CTLA-4.
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DOI：
10.3389/fimmu.2020.600000
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发表时间：
2020
影响因子：
7.3
通讯作者：
Sansom DM
中科院分区：
文献类型：
--
作者：
Halliday N;Williams C;Kennedy A;Waters E;Pesenacker AM;Soskic B;Hinze C;Hou TZ;Rowshanravan B;Janman D;Walker LSK;Sansom DM
CD 80和CD 86在抗原递呈细胞上表达，并需要与其共享受体CD 28接合，以共同刺激CD 4 T细胞。目前还不清楚为什么两个具有重叠作用的刺激配体已经进化。CD 80和CD 86也结合调节分子CTLA-4。我们探讨了CD 80和CD 86在CD 4 + FoxP 3+调节性T细胞（Treg）的稳态和增殖中的作用，Treg组成性表达高水平的CTLA-4，但严重依赖于CD 28信号。我们观察到，CD 86是调节表型的Treg增殖、存活和维持的主要配体，CTLA-4、ICOS和OX 40的表达更高。我们还探索了CD 80-CD 28相互作用是否受到CTLA-4的特异性损害，并发现抗体阻断、CTLA-4的临床缺陷和CTLA-4的CRISPR-Cas9缺失都改善了CD 80刺激后的Treg存活。总之，我们的数据表明，CD 86是Treg稳态的主要共刺激配体，尽管其对CD 28的亲和力较低，因为CD 80-CD 28相互作用被高水平的CTLA-4选择性地削弱。这些数据表明CTLA-4在通过直接竞争CD 80调节CD 28共刺激中的细胞内在作用，并表明在高水平CTLA-4存在下，CD 80和CD 86在CD 4 T细胞的CD 28共刺激中具有离散作用。
CD80 and CD86 are expressed on antigen presenting cells and are required to engage their shared receptor, CD28, for the costimulation of CD4 T cells. It is unclear why two stimulatory ligands with overlapping roles have evolved. CD80 and CD86 also bind the regulatory molecule CTLA-4. We explored the role of CD80 and CD86 in the homeostasis and proliferation of CD4+FoxP3+ regulatory T cells (Treg), which constitutively express high levels of CTLA-4 yet are critically dependent upon CD28 signals. We observed that CD86 was the dominant ligand for Treg proliferation, survival, and maintenance of a regulatory phenotype, with higher expression of CTLA-4, ICOS, and OX40. We also explored whether CD80-CD28 interactions were specifically compromised by CTLA-4 and found that antibody blockade, clinical deficiency of CTLA-4 and CRISPR-Cas9 deletion of CTLA-4 all improved Treg survival following CD80 stimulation. Taken together, our data suggest that CD86 is the dominant costimulatory ligand for Treg homeostasis, despite its lower affinity for CD28, because CD80-CD28 interactions are selectively impaired by the high levels of CTLA-4. These data suggest a cell intrinsic role for CTLA-4 in regulating CD28 costimulation by direct competition for CD80, and indicate that that CD80 and CD86 have discrete roles in CD28 costimulation of CD4 T cells in the presence of high levels of CTLA-4.
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