期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：42
页码：21120-21130
DOI：10.1073/pnas.1901382116
出版社：The National Academy of Sciences of the United States of America
摘要：Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their heterotrimeric receptors share their β- and γ c -chains, but have distinct α-chains. Anti–IL-2Rα (daclizumab) therapy targeting cell surface-expressed receptor subunits to inhibit T cell proliferation has only brought limited success in adult T cell leukemia/lymphoma (ATL) and in multiple sclerosis. We asked whether IL-2R subunits could already preassemble and signal efficiently in the endoplasmic reticulum (ER) and the Golgi. A combination of daclizumab and anti–IL-2 efficiently blocked IL-2–induced proliferation of IL-2–dependent wild-type (WT) ATL cells but not cells transfected with IL-2, suggesting that in IL-2–producing cells signaling may already take place before receptors reach the cell surface. In the Golgi fraction isolated from IL-2–producing ATL cells, we detected by Western blot phosphorylated Jak1, Jak3, and a phosphotyrosine signal attributed to the γ c -chain, which occurred at much lower levels in the Golgi of WT ATL cells. We expressed EGFP- and mCherry-tagged receptor chains in HeLa cells to study their assembly along the secretory pathway. Confocal microscopy, Förster resonance energy transfer, and imaging fluorescence cross-correlation spectroscopy analysis revealed partial colocalization and molecular association of IL-2 (and IL-15) receptor chains in the ER/Golgi, which became more complete in the plasma membrane, further confirming our hypothesis. Our results define a paradigm of intracellular autocrine signaling and may explain resistance to antagonistic antibody therapies targeting receptors at the cell surface..
关键词：adult T cell leukemia;lymphoma ; antiproliferative antibody therapy ; autocrine signaling ; IL;2;15 receptor preassembly ; Förster resonance energy transfer
