Effect of transforming growth factor-beta on early and late activation events in human T cells.
Transforming growth factors-beta (TGF-beta) modulate immune responses by inhibiting the proliferation of normal T lymphocytes. To examine the mechanism(s) of this inhibition, we studied the effect of TGF-beta 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 1 (0.5 to 10 ng/ml) 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-2R alpha, IL-2R beta, and transferrin receptor) were not affected by TGF-beta 1. Total cellular RNA synthesis and cell size after T cell stimulation were also not affected by TGF-beta 1. However, TGF-beta 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 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 1 inhibits T cell proliferation by down-regulating predominantly IL-2-mediated proliferative signals.
Ahuja
S S
SS
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Paliogianni
F
F
Yamada
H
H
Balow
J E
JE
Boumpas
D T
DT
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D010766:Phosphorylation; D015375:Receptors, Interleukin-2 / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D014443:Tyrosine