P. Hollsberg et al., HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE I-INDUCED T-CELL ACTIVATION - RESISTANCE TO TGF-BETA-1-INDUCED SUPPRESSION, The Journal of immunology, 153(2), 1994, pp. 566-573
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.