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The Role of Lymphotoxin in Target Cell Destruction Induced by Mitogen-Activated Human Lymphocytes in Vitro

II. The Correlation of Temperature and Trypsin-Sensitive Phases of Lymphotoxin-Induced and Lymphocyte-Mediated Cytotoxicity¹

From the Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92664

Abstract

The in vitro destruction of phytohemagglutinin (PHA) coated L cells by non-immune human lymphocytes was resolved into two distinct phases—lymphocyte dependent and lymphocyte independent. The initial or lymphocyte-dependent phase occurred within the first 2 hr and proceeded equally well at 34 and 37°C. The amount of lymphotoxin (LT) secreted by PHA-activated human lymphocytes in vitro to PHA stimulation was the same at 34 and 37°C. Antiserum and complement inactivation of the aggressor lymphocytes at various intervals revealed that target cell lysis was lymphocyte independent. However, the latter phase was temperature dependent, i.e., proceeding at the permissive temperature of 37°C, but inhibited at the restrictive temperature of 34°C. Further experiments revealed that LT-induced destruction had the same temperature sensitivity as target cell cytolysis occurring during the lymphocyte-independent step. Trypsin treatment of target cells during an early period of the lymphocyte-independent phase protected the target cell from subsequent death, indicating the aggressor lymphocyte has deposited a cytotoxic effector material on its surface. These results suggest the lymphocyte-dependent stage involves the processes required for the induction of LT synthesis and secretion. The actual cytolysis occurring during the lymphocyte-independent stage may be caused by LT or LT-like material(s) deposited on the target cell surface by the mitogen-activated human lymphocyte.

Footnotes

¹ This research was supported by Grant AI 09460-04, from the Institute of Allergy and Infectious Diseases, NIH; Grant IM-32, from the American Cancer Society, and Grant 1883, from the Rheumatic Diseases Research Foundation.

² G. A. Granger is supported by a career award from N.I.A.I.D. of the NIH.