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Effect of Phorbol Esters on Alloimmune Cytolysis¹

Department of Pathology, University of Connecticut Health Center, Farmington, Connecticut 06032

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) profoundly affects cytolytic T-lymphocyte activity. Alloimmune C57BL/6 (H-2b anti-H-2d) cytolytic splenocytes treated with TPA, 0.3 to 3.0 ng/ml, killed specific P815 (H-2d) targets significantly better than did untreated controls as measured in a 4-hr ⁵¹Cr release microcytotoxicity assay. Higher concentrations of TPA in the 30- to 100-ng/ml range significantly inhibited cytolytic function. The non-tumor-promoting analog, 4-phorbol-12,13-didecanoate, failed to affect killing at all doses tested. TPA-induced augmentation of cytolytic function requires an immunologically sensitized splenocyte population, since normal nonimmunized splenocytes treated with TPA did not kill target cells. Furthermore, treatment of splenocytes with anti-Thy 1.2 antibody and complement abrogated killing, indicating that T-lymphocytes mediate the killing. The TPA-induced effect does not require macrophage-like cells, since augmented killing occurred despite the removal of glass-adherent or iron-phagocytosing cells. Finally, the cytolytically augmented effector cells remain immunologically specific, since the nonspecific targets, syngeneic EL4 (H-2b) and third-party L929 (H-2k), are not killed. Thus, low levels of TPA augment the cytolytic ability of alloimmune T-lymphocytes against their specific target cells.

¹ Supported by Grant ACS-187 from the American Cancer Society.

² Supported by USPHS Predoctoral Fellowship AI-07080. To whom requests for reprints should be addressed.

Received 5/ 8/80. Accepted 9/ 9/82.

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