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

Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):21120-21130. doi: 10.1073/pnas.1901382116. Epub 2019 Sep 30.


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.

Keywords: Förster resonance energy transfer; IL-2/15 receptor preassembly; adult T cell leukemia/lymphoma; antiproliferative antibody therapy; autocrine signaling.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / physiology*
  • Endoplasmic Reticulum / metabolism*
  • Golgi Apparatus / metabolism*
  • HeLa Cells
  • Humans
  • Interleukin-15 / metabolism
  • Interleukin-2 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / metabolism*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 3 / metabolism
  • Receptors, Interleukin-15 / metabolism
  • Signal Transduction / physiology


  • Interleukin-15
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Interleukin-15
  • Janus Kinase 1
  • Janus Kinase 3