Human T cell lymphotropic virus type I-induced T cell activation. Resistance to TGF-beta 1-induced suppression.
T cell proliferation is potently suppressed by TGF-beta during the G1 phase of the cell cycle. The mechanism appears to involve inhibition of cell cycle kinases that phosphorylate the retinoblastoma protein (pRb), a key regulator of cell cycle progression from G1 to S phase. Although productive infection with the human T cell lymphotropic virus type I (HTLV-I) induces T cell activation, it also, paradoxically, leads to increased production of TGF-beta. To investigate whether infection by HTLV-I conferred resistance to TGF-beta in non-immortalized T cells, we generated T cell clones from patients with HTLV-I myelopathy by direct single cell cloning. Here we report that HTLV-I-infected but not uninfected T cell clones have hyperphosphorylated pRb consistent with viral-induced T cell activation. Furthermore, the HTLV-I-infected T cells were resistant to growth suppression by rTGF-beta 1 and this correlated with the inability of TGF-beta 1 to prevent hyperphosphorylation of pRb. However, when spontaneously proliferating HTLV-I-infected T cell clones were further stimulated by cross-linking of the CD3/TCR complex, the superimposed proliferation was significantly inhibited by TGF-beta 1, suggesting that the TGF-beta 1 signaling pathway was intact. Together these findings suggest that HTLV-I induces T cell activation through a pathway that is insensitive to TGF-beta 1. This may have implications for the altered immune regulation in patients with HTLV-I myelopathy.
Center for Neurologic Diseases, Brigham & Women's Hospital, Boston, MA 02115.
P
P
Höllsberg
L J
LJ
Ausubel
D A
DA
Hafler
D001483:Base Sequence; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D012333:RNA, Messenger; D012367:RNA, Viral; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta