The role of receptor-ligand endocytosis and degradation in interleukin-2 signaling and T-lymphocyte proliferation.
The specific intracellular signaling pathways for interleukin-2 (IL-2) that lead to delivery of the proliferative stimulus are currently unknown. We and others have excluded signaling pathways used by other growth factors and by the antigen-specific T-cell receptor, such as increased intracellular Ca2+ concentrations, activation of protein kinase C, or ion transport across the plasma membrane. One feature of IL-2 signaling that may be important in delivery of the proliferative stimulus is endocytosis and processing of the lymphokine receptor-ligand complex. In this study we examined these steps in receptor signaling by mouse CTLL-2 cells and human OKT3-activated T-cells using monoclonal antibodies specific for the 55 kDa alpha-subunit of the IL-2R that allow IL-2 binding but block endocytosis, and with lysosomotrophic amines that selectively inhibit receptor mediated endocytosis and/or processing of IL-2. Our results demonstrate that these inhibitors block receptor endocytosis, ligand degradation, c-fos protooncogene activation, and ultimately proliferation of the IL-2-dependent T-cell line, CTLL-2. In heterogeneous populations of activated human T cells the lysosomotrophic amines demonstrated a greater inhibition of degradation than of endocytosis. These observations support the hypothesis that IL-2/IL-2R endocytosis and ligand/receptor processing or degradation may be important steps in lymphokine signal transduction.
Legrue
S J
SJ
Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030.
Sheu
T L
TL
Chernajovsky
Y
Y
D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000502:physiology*; D008024:Ligands; D008744:Methylamines / Q000494:pharmacology; D011319:Primaquine / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology*
D007376:Interleukin-2; D008024:Ligands; D008744:Methylamines; D011948:Receptors, Antigen, T-Cell; D002738:Chloroquine; C027451:methylamine; D011319:Primaquine