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Inhibition of Tumor-specific Cytotoxic T-Lymphocyte Responses by Transforming Growth Factor ß₁¹

Department of Microbiology and Immunology [T. H. I., B. M. S., H. D. B.] and Department of Surgery and Massey Cancer Center [S. K. H., B. M. S., S. K. B., H. D. B.], Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Transforming growth factor ß (TGF-ß) is a potent immunosuppressive cytokine that is produced by neoplastic and normal cells. It has not been demonstrated directly, however, that TGF-ß can inhibit antigen-specific T-cell responses to tumor cells in vitro. We show here that generation of antitumor cytotoxic T-lymphocyte (CTL) activity in mixed-lymphocyte tumor cultures of splenocytes from DBA/2 mice immunized with the syngeneic P815 mastocytoma + Corynebacterium parvum was consistently and profoundly inhibited when 0.675 to 10 ng/ml of TGF-ß were added on Day 0 of culture. TGF-ß added on Day 1 or later had little or no effect. In contrast to the results with P815 immune mice, mixed-lymphocyte tumor cultures established with splenocytes from P815 tumor-bearing hosts showed variable degrees of inhibition by TGF-ß, depending on the stage of the ongoing in vivo immune response. Addition of recombinant murine tumor necrosis factor (1,000 or 10,000 units/ml) partially reversed inhibition of CTL responses by TGF-ß, while recombinant interleukin 2 nearly completely reversed the suppression. These data indicate that one level at which TGF-ß may act to inhibit mixed-lymphocyte tumor cultures is that of cytokine production. To determine whether TGF-ß also has any direct effect on CTL, P815-specific CTL clones derived from tumor-bearing host mice were utilized. We found that proliferation of rested CTL clones in response to tumor cells + interleukin 2 was inhibited by 5 ng/ml of TGF-ß, while the interleukin 2-dependent reactivation of cytolytic activity was not affected by TGF-ß. In contrast to rested CTL, when TGF-ß was added to cultures of previously activated CTL, proliferation was not inhibited. These data demonstrate that TGF-ß has profound inhibitory effects on the in vitro generation of effector CTL from tumor-specific murine splenocytes, and this inhibition may be an indirect result of suppressed cytokine production as well as a direct antiproliferative effect on CTL.

¹ This research was supported by Grants CA48075 and in part by Grant AI-25044 from the Department of Health and Human Services, NIH. T. H. I. is a recipient of a Medical Scholars Award from the A. D. Williams Foundation and a scholarship award from the Norfolk Foundation.

² To whom requests for reprints should be addressed.

Received 7/18/91. Accepted 12/20/91.

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