Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation.
Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation.
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DOI：
10.1038/s41590-022-01289-w
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发表时间：
2022-09
影响因子：
30.5
通讯作者：
Sansom, David M.
中科院分区：
文献类型：
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作者：
Kennedy, Alan;Waters, Erin;Rowshanravan, Behzad;Hinze, Claudia;Williams, Cayman;Janman, Daniel;Fox, Thomas A.;Booth, Claire;Pesenacker, Anne M.;Halliday, Neil;Soskic, Blagoje;Kaur, Satdip;Qureshi, Omar S.;Morris, Emma C.;Ikemizu, Shinji;Paluch, Christopher;Huo, Jiandong;Davis, Simon J.;Boucrot, Emmanuel;Walker, Lucy S. K.;Sansom, David M.
CD 28和CTLA-4（CD 152）在调节T细胞免疫、分别平衡T细胞应答的激活和抑制中起重要作用。虽然两种受体共享相同的配体，CD 80和CD 86，但对两种不同配体的具体要求仍然不清楚。在本研究中，我们证明，虽然CTLA-4靶向CD 80和CD 86通过transendocytosis破坏，这一过程中的结果在不同的命运CTLA-4本身。在CD 80的存在下，CTLA-4保持配体结合，并且被泛素化并通过晚期内体和溶酶体运输。相反，在CD 86的存在下，CTLA-4以pH依赖性的方式分离并再循环回到细胞表面以允许进一步的转内吞作用。此外，我们鉴定了引起自身免疫性疾病的临床相关突变，其通过影响CTLA-4再循环或CD 86结合选择性地破坏CD 86转内吞作用。这些观察结果为两种不同的配体提供了理论基础，并表明CTLA-4介导的CD 86转内吞作用的缺陷与自身免疫相关。抑制性受体CTLA-4识别相对抗原呈递细胞上的两种配体，CD 80和CD 86。Sansom及其同事表明CTLA-4通过转内吞作用捕获配体，因此低亲和力CD 86在低pH下释放CTLA-4以促进CTLA-4再循环;然而，高亲和力CD 80保持结合并靶向CTLA-4进行泛素化和破坏。
CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity. The inhibitory receptor CTLA-4 recognizes two ligands on opposing antigen-presenting cells, CD80 and CD86. Sansom and colleagues show CTLA-4 captures ligands by transendocytosis, whereupon low-affinity CD86 releases CTLA-4 at low pH to promote CTLA-4 recycling; however, high-affinity CD80 remains bound and targets CTLA-4 for ubiquitination and destruction.
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影响因子：
30.5
作者：
通讯作者：
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B7-1和B7-2共刺激配体的比较分析：表达和功能。
DOI：
10.1084/jem.180.2.631
发表时间：
1994-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hathcock KS;Laszlo G;Pucillo C;Linsley P;Hodes RJ
通讯作者：
Hodes RJ
DOI：
10.1126/science.1202947
发表时间：
2011-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Qureshi OS;Zheng Y;Nakamura K;Attridge K;Manzotti C;Schmidt EM;Baker J;Jeffery LE;Kaur S;Briggs Z;Hou TZ;Futter CE;Anderson G;Walker LS;Sansom DM
通讯作者：
Sansom DM
DOI：
10.4049/jimmunol.1102885
发表时间：
2012-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Good-Jacobson KL;Song E;Anderson S;Sharpe AH;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
14.8
作者：
通讯作者：
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