Significance Interleukin-2 (IL-2), a cytokine produced by activated T cells, acting in a paracrine/autocrine fashion, is essential for T cell proliferation. In adult T cell leukemia (ATL) and in autoimmune/graft-vs.-host diseases, anti–IL-2Rα antibody therapies were established to inhibit proliferation, with only limited success. We demonstrated that IL-2/15 receptors start to assemble in the endoplasmic reticulum/Golgi and demonstrated signaling by Jak1/Jak3 in the Golgi. Thus, in T cells also producing IL-2 (e.g., ATL cells), signaling can already take place before receptors reach cell membranes. This scenario explains resistance to antibody therapies targeting receptors at cell surfaces. Our study sheds light on an autocrine signaling mechanism, in which an intracellularly synthesized ligand activates its receptor en route toward the cell surface.