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Immunoregulation and Production of Tumor Necrosis Factor by Human Thymocytes¹

Department of Pharmacology and the Kaplan Cancer Center, New York University Medical Center, New York, New York 10016

We have provided evidence that tumor necrosis factor (TNF-) enhances the proliferation and the state of activation of human thymocytes cultured with concanavalin A or interleukin 2 (IL-2), as evidenced by an increase in the expression of the c-myc gene and the gene of the IL-2 receptor (-chain, Tac antigen) and by the expression of Tac antigen on the cell surface. Our observations suggest that TNF- interacts with IL-2 and with another factor(s) which is induced in the course of activation by concanavalin A, since the immunosuppressant drug cyclosporin A-, which inhibits thymocyte activation, prevents the effect of TNF- on thymocytes activated with concanavalin A, whereas anti-Tac, which prevents the binding of IL-2 to its receptor without affecting the production of IL-2 or the expression of IL-2-specific mRNA, inhibits proliferation only partially. By contrast, anti-Tac inhibits the response to TNF- of thymocytes induced with IL-2 completely. These observations show that TNF- exerts a potentially important immunoregulatory effect in synergy with IL-2 on thymocytes, which could contribute to tumor rejection. In addition, we show that activated human thymocytes express the TNF- gene and that the expression of this gene is inhibited by cyclosporin A and dexamethasone.

¹ This work was supported by NIH Grant RO 1 CA 33653.

² To whom requests for reprints should be addressed, at Department of Pharmacology, New York University Medical Center, 550 First Ave., New York, NY 10016.

³ Supported in part by a grant of the Deutsche Forschungs Gemeinschaft Stipendium Schl 251/1-1.

Received 12/14/88. Revised 3/16/89. Accepted 3/30/89.