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Research Article Free access | 10.1172/JCI117215

Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo.

C Ferran, F Dautry, S Mérite, K Sheehan, R Schreiber, G Grau, J F Bach, and L Chatenoud

Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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Institut National de la Sante et de la Recherche Medicale, U-25, Hôpital Necker, Paris, France.

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First published May 1, 1994 - More info

Published in Volume 93, Issue 5 on May 1, 1994
J Clin Invest. 1994;93(5):2189–2196. https://doi.org/10.1172/JCI117215.
© 1994 The American Society for Clinical Investigation
First published May 1, 1994 - Version history
Abstract

De novo expression of TNF, IFN gamma, IL-3, IL-4, and IL-6 genes was initiated rapidly by treatment of mice with anti-CD3. A specific feature 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. Pretreatment with anti-TNF did not affect anti-CD3-triggered TNF mRNA expression in T cells. In contrast, in vivo and in vitro anti-TNF treatment upregulated anti-CD3-induced IFN gamma mRNA expression and inhibited IL-4 mRNA expression. These latter effects were not dependent on TNF neutralization: pretreatment with soluble recombinant 55-kD TNF receptor (TBPI) as an alternative TNF-neutralizing agent did not modify the anti-CD3-induced cytokine profile. These results suggest that a direct interaction between anti-TNF and T cell membrane-anchored TNF could account for the observed modulation of cytokine gene expression. The increased expression of INF gamma mRNA observed in anti-TNF-treated animals correlated with a decrease in IL-3 and IL-6 mRNA expression. Conversely, IFN gamma 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 existence, in the anti-CD3-induced cytokine cascade, of IFN gamma-dependent regulation of IL-3 production, which in turn modulates IL-6 production.

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