Effect of Transforming Growth Factor-Beta on Early and Late Activation Events inHuman T Cells. (Reannouncement with New Availability Information)

摘要

Transforming growth factors-Beta (TGF-Beta) modulate immune responses byinhibiting the proliferation of normal T lymphocytes. To examine the mechanism(s) of this inhibition, we studied the effect of TGF-Beta sub 1 on selected events associated with the initiation and progression of the T lymphocyte cell cycle. Human peripheral blood T cells were stimulated with anti-CD3 mAb, PHA, PMA, or ionomycin, alone or in combination. TGF-Beta sub q (0.5 to 10 n/mi) partially inhibited the tyrosine phosphorylation of a 100-kDa protein, but not the calcium influx when cells were stimulated via TCR. Nuclear transcription of early activation genes (c-fos, c-jun, and c-myc) as determined by nuclear run-off assays, and steady state mRNA levels and/or protein products of intermediate activation genes (IL-2, IL-2Ra, IL-2R Beta, and transferrin receptor) were not affected by TGF-Beta sub 1. Total cellular RNA synthesis and cell size after T cell stimulation were also not affected by TGF-PI. However, TGF-Beta sub 1 inhibited the IL-2-dependent proliferation of Con A lymphoblasts by -50%. This inhibition was associated with the down-regulation of IL-2-mediated tyrosine phosphorylation of proteins of 120, 100, 85, 75, and 50 kDa. TGF-Beta sub 1 also inhibited the IL-2-dependent phosphorylation of the retinoblastoma susceptibility gene product, which plays an important role in cell cycle progression. These results suggest that TGF-Beta sub 1 inhibits T cell proliferation by down-regulating predominantly IL-2-mediated proliferative signals....T lymphocyte, Transforming growth factor beta, Gene regulation, Interleukin-2 production, Calcium.