Human T-cell lymphotropic virus type 1 p12I enhances interleukin-2 production during T-cell activation.
Human T-cell lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL) and a variety of lymphoproliferative disorders. The early virus-cell interactions that determine a productive infection remain unclear. However, it is well recognized that T-cell activation is required for effective retroviral integration into the host cell genome and subsequent viral replication. The HTLV-1 pX open reading frame I encoding protein, p12(I), is critical for the virus to establish persistent infection in vivo and for infection in quiescent primary lymphocytes in vitro. p12(I) localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus, increases intracellular calcium and activates nuclear factor of activated T cells (NFAT)-mediated transcription. To clarify the function of p12(I), we tested the production of IL-2 from Jurkat T cells and peripheral blood mononuclear cells (PBMC) expressing p12(I). Lentiviral vector expressed p12(I) in Jurkat T cells enhanced interleukin-2 (IL-2) production in a calcium pathway-dependent manner during T-cell receptor (TCR) stimulation. Expression of p12(I) also induced higher NFAT-mediated reporter gene activities during TCR stimulation in Jurkat T cells. In contrast, p12 expression in PBMC elicited increased IL-2 production in the presence of phorbal ester stimulation, but not during TCR stimulation. Finally, the requirement of ER localization for p12(I)-mediated NFAT activation was demonstrated and two positive regions and two negative regions in p12(I) were identified for the activation of this transcription factor by using p12(I) truncation mutants. These results are the first to indicate that HTLV-1, an etiologic agent associated with lymphoproliferative diseases, uses a conserved accessory protein to induce T-cell activation, an antecedent to efficient viral infection.
D020816:Amino Acid Motifs; D001665:Binding Sites; D018106:CD28 Antigens / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium