ANTITUMOR NECROSIS FACTOR MODULATES ANTI-CD3-TRIGGERED T-CELL CYTOKINE GENE-EXPRESSION IN-VIVO

De novo expression of TNF, IFN gamma, IL-3, IL-4, and IL-6 genes was i nitiated rapidly by treatment of mice with anti-CD3. A specific featur e of this reaction was that TNF was derived exclusively from T cells. TNF was produced both as a mature soluble trimeric protein and as a 26 -kD anti-TNF-reactive protein compatible with membrane-anchored TNF. P retreatment with anti-TNF did not affect anti-CD3-triggered TNF mRNA e xpression in T cells. In contrast, in vivo and in vitro anti-TNF treat ment upregulated anti-CD3-induced IPN gamma mRNA expression and inhibi ted IL-4 mRNA expression. These latter effects were not dependent on T NF neutralization: pretreatment with soluble recombinant 55-kD TNF rec eptor (TBPI) as an alternative TNF-neutralizing agent did not modify t he anti-CD3-induced cytokine profile. These results suggest that a dir ect interaction between anti-TNF and T cell membrane-anchored TNF coul d account for the observed modulation of cytokine gene expression. The increased expression of INF gamma mRNA observed in anti-TNF-treated a nimals correlated with a decrease in IL-3 and IL-6 mRNA expression. Co nversely, IFN I blockade by a neutralizing anti-IFN gamma mAb led to a substantial increase in both IL-3 and IL-6 gene expression induced by anti-CD3. Taken together, these results strongly argue for the existe nce, in the anti-CD3-induced cytokine cascade, of IFN gamma-dependent regulation of IL-3 production, which in turn modulates IL-6 production .