HTLV-1 p12I protein enhances STAT5 activation and decreases the interleukin-2 requirement for proliferation of primary human peripheral blood mononuclear cells

The p12I protein, encoded by the pX open reading frame I of the human T-lymphotropic virus type 1 (HTLV-1), is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi. Although p12I contains 4 minimal proline-rich, src homology 3–binding motifs (PXXP), a characteristic commonly found in proteins involved in signaling pathways, it has not been known whether p12I has a role in modulating intracellular signaling pathways. This study demonstrated that p12I binds to the cytoplasmic domain of the interleukin-2 receptor (IL-2R) β chain that is involved in the recruitment of the Jak1 and Jak3 kinases. As a result of this interaction, p12I increases signal transducers and activators of transcription 5 (STAT5) DNA binding and transcriptional activity and this effect depends on the presence of both IL-2R β and γc chains and Jak3. Transduction of primary human peripheral blood mononuclear cells (PBMCs) with a human immunodeficiency virus type 1–based retroviral vector expressing p12I also resulted in increased STAT5 phosphorylation and DNA binding. However, p12I could increase proliferation of human PBMCs only after stimulation of T-cell receptors by treatment of cells with low concentrations of αCD3 and αCD28 antibodies. In addition, the proliferative advantage of p12I-transduced PBMCs was evident mainly at low concentrations of IL-2. Together, these data indicate that p12I may confer a proliferative advantage on HTLV-1–infected cells in the presence of suboptimal antigen stimulation and that this event may account for the clonal proliferation of infected T cells in vivo.