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 G(1 ) 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 G(1) to S phase. Although productive infection with the human T cell lymphotropic virus type I (HTLV-I) induces T cell activation, it also, paradoxically, le ads to increased production of TCF-beta. To investigate whether infect ion by HTLV-I conferred resistance to TCF-beta in non-immortalized T c ells, 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 rTCF-beta 1 and this correlated with the inability of TGF-beta 1 to prevent hyperphosphoryl ation of pRb. However, when spontaneously proliferating HTLV-I-infecte d T cell clones were further stimulated by cross-linking of the CD3/TC R complex, the superimposed proliferation was significantly inhibited by TGF-beta 1, suggesting that the TGF-beta 1 signaling pathway was in tact. Together these findings suggest that HTLV-I induces T cell activ ation through a pathway that is insensitive to TGF-beta 1. This may ha ve implications for the altered immune regulation in patients with HTL V-I myelopathy.