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Lymphokine-activated Killer Cells in Rats: Analysis of Progenitor and Effector Cell Phenotype and Relationship to Natural Killer Cells¹

Pittsburgh Cancer Institute and Departments of Pathology (N.L.V., R.B.H., M.W.O., D.V.C., J.C.H.), Medicine (R.B.H.), and Surgery (R.R.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and Biological Response Modifiers Program, NCI-Frederick Cancer Research Facility, Frederick, Maryland 21701 [C. W. R.]

The progenitor and effector cell phenotype of lymphokine-activated killer (LAK) cells generated in F344 rats by recombinant human interleukin 2 (IL-2) (rIL-2) were analyzed. Highly purified populations of peripheral blood large granular lymphocytes (LGL) exhaustively depleted of T-cells were fully capable of generating high levels of LAK activity by 3 to 5 days in culture while purified populations of resting T-cells devoid of LGL could not generate LAK activity. This pure population of LGL expressed surface markers characteristic of rat natural killer (NK) cells [i.e., OX8⁺, asialomonoganglioside (asialo-GM₁⁺), laminin⁺, OX19^-, R1-3B3^-, W3/25^-, Ia^-, surface immunoglobulin negative (SIg^-)]. Further evidence that NK cells were the progenitors of cells with LAK activity was obtained by treatment of spleen or peripheral blood lymphocytes with anti-laminin or anti-asialo-G_M1 antibodies plus complement or with the lysosomotropic agent L-leucine methyl ester. These treatments effectively depleted LGL/NK cell activity and the subsequent generation of rIL-2-induced LAK activity. Analysis of the LAK effector phenotype by cell sorting demonstrated that the majority of cells with LAK activity were OX8⁺, asialo-G_M1⁺, laminin⁺, OX6⁺, OX19^-, R1-3B3^-, W3/25^-, and SIg^-. Furthermore, treatment of LAK cells with L-leucine methyl ester also significantly reduced their cytolytic activity. Thus, the LAK effector cells were also LGL and expressed surface marker characteristic of activated NK cells and not those of mature T- or B-cells.

The proliferative response of rat spleen or blood lymphocytes to rIL-2 appeared to be primarily associated with LGL/NK cells since depletion of NK cells by anti-asialo-G_M1 or anti-laminin antibody plus complement or by L-leucine methyl ester significantly (P < 0.001) reduced the incorporation of [³H]thymidine into DNA. In contrast, depletion of T-cells (by anti-T-cell antibody plus complement) did not significantly affect rIL-2-induced proliferation. Similarly, T-cell-depleted, highly purified populations of LGL gave substantial proliferative responses to rIL-2.

These studies clearly indicate that in the rat, the major cell population activated by rIL-2 is the LGL/NK cell and these cells appear to represent the major population of cells in blood or spleen which generate broad antitumor (LAK) cytotoxicity.

¹ Supported in part by Grants CA 43765 and HL 37638 from the NIH.

² Present address: Institute of Oncology and Radiology, Pasterova 14, 11000 Belgrade, Yugoslavia.

³ To whom requests for reprints should be addressed, at Pittsburgh Cancer Institute, 3343 Forbes Avenue, Pittsburgh, PA 15213.

Received 7/ 2/87. Revised 11/ 6/87. Accepted 11/18/87.

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