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Lymphokine-activated Killer Activity in Long-Term Cultures with Anti-CD3 plus Interleukin 2: Identification and Isolation of Effector Subsets¹

Immunobiology Research Center, University of Minnesota Hospital and Clinic, Minneapolis, Minnesota 55455

Peripheral blood lymphocytes cultured in recombinant interleukin 2 during 3 to 5 days (short-term cultures) develop the ability to lyse natural killer-resistant tumor lines and fresh tumor cells, i.e., express lymphokine-activated killer (LAK) function. Phenotypic analysis has shown these cells to be natural killer cells, i.e., CD16⁺ and/or Leu 19⁺ cells. CD3⁺,CD16^- T-cells, instead, develop very low LAK function in these cultures.

We recently reported the development of long-term (up to 21 days) cultured cells with LAK activity by stimulation with OKT3 + interleukin 2(IL2). These culture conditions repeatedly resulted in a several hundredfold expansion in cell number. Specific LAK activity on Day 14 of culture was comparable to that of 3-day LAK cultures and could be further enhanced by the addition of interleukin 1ß, ß-, or -interferon. Total LAK activity was greatly increased in OKT3 + IL2 cultures over that found in short-term cultures.

Isolation of effectors mediating LAK function in long-term cultures stimulated with OKT3 + IL2 showed that both CD3⁺,CD16^- cells and CD16⁺,CD3^- cells tested on Day 14 of culture expressed equivalent levels of LAK activity as shown by lysis of natural killer-resistant targets, HL60 and Daudi. Further dissection of the subpopulations developing LAK activity demonstrated that, in addition to CD16⁺,CD3^- cells, CD3⁺, CD4^-,CD8^- cells and Leu 19⁺,CD3^-,CD16^- cells also developed high LAK activity in long-term cultures with OKT3 + IL2. Further, long-term culture with OKT3 + IL2 induced increases in the numbers not only of CD3⁺,CD4^-,CD8^- cells but also of CD16⁺,CD3^- and Leu 19⁺,CD3^-,CD16^- cells. Although there is a significant increase in the number of CD3⁺,CD8⁺ cells, neither these, nor the CD3⁺,CD4⁺ cells, mediate LAK activity to the same extent as the populations mentioned above.

¹ This is Paper 478 from the Jordan Bazelon Laboratories of the Immunobiology Research Center, Box 724, University of Minnesota, Hospital and Clinic, Harvard Street at East River Road, Minneapolis, MN 55455. This work was supported in part by NIH Grants AI 17687, AI 18326, AI 19007, AI 22682, AI 72626, and CA 47097.

² To whom requests for reprints should be addressed at: Immunobiology Research Center, Box 724 UMHC, 420 Delaware St. S.E., Minneapolis, MN 55455.

Received 4/ 1/88. Revised 8/ 1/88. Revised 11/ 7/88. Accepted 11/14/88.

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