IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti–IL-2Rα therapies

Julianna Volkó, Ádám Kenesei, Meili Zhang, Péter Várnai, Gábor Mocsár, Michael N. Petrus, Károly Jambrovics, Zoltán Balajthy, Gabriele Müller, Andrea Bodnár, Katalin Tóth, Thomas A. Waldmann, György Vámosi

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Abstract

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 γc-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 γc-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.

Original languageEnglish
Pages (from-to)21120-21130
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number42
DOIs
Publication statusPublished - Oct 15 2019

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Keywords

  • Adult T cell leukemia/lymphoma
  • Antiproliferative antibody therapy
  • Autocrine signaling
  • Förster resonance energy transfer
  • IL-2/15 receptor preassembly

ASJC Scopus subject areas

  • General

Cite this

Volkó, J., Kenesei, Á., Zhang, M., Várnai, P., Mocsár, G., Petrus, M. N., Jambrovics, K., Balajthy, Z., Müller, G., Bodnár, A., Tóth, K., Waldmann, T. A., & Vámosi, G. (2019). IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti–IL-2Rα therapies. Proceedings of the National Academy of Sciences of the United States of America, 116(42), 21120-21130. https://doi.org/10.1073/pnas.1901382116