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Cellular Interactions in Effector Cell Generation and Tumor Regression Mediated by Anti-CD3/Interleukin 2-activated Tumor-draining Lymph Node Cells¹

Oncology Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109

Previous studies have demonstrated that progressive growth of the weakly immunogenic MCA 106 murine sarcoma stimulated, in the draining lymph nodes, the production of tumor-sensitized but not fully functional preeffector lymphocytes. These lymphocytes could develop into specific immune effector cells after sequential in vitro activation with anti-CD3 monoclonal antibody and interleukin 2 (IL-2). In this study, we analyzed cellular requirements for in vivo sensitization of preeffector cells, for generation of immune effector cells by the method of anti-CD3/IL-2 activation, and for adoptive immunotherapy mediated by activated cells. By selective depletion of T-cell subsets in vivo, we found that tumor regression after systemic adoptive immunotherapy required the collaboration of activated CD4⁺ and CD8⁺ cells. It was further demonstrated that CD8⁺ immune cells alone could mediate antitumor effects if exogenous IL-2 was provided in vivo. These results suggest that CD8⁺ cells served as immediate effector cells, whereas CD4⁺ immune cells provided a helper function via the secretion of IL-2. During in vitro anti-CD3/IL-2 activation, generation of effector cells depended on the collaborative interaction between previously sensitized CD4⁺ and CD8⁺ preeffector cells. At the stage of in vitro activation, the addition of IL-2 could not substitute the function of CD4⁺ cells. We next examined whether the sensitization of preeffector cells in the draining lymph nodes required cellular interactions between CD4⁺ and CD8⁺ T-cells. By in vivo depletion of T-cell subsets during tumor growth, we found that CD4⁺ cells were sensitized independently of CD8⁺ cells. More interestingly, in vivo sensitization of CD8⁺ preeffector cells also occurred independently in the absence of a CD4⁺ helper cell response. The lack of T-cell-T-cell interactions in vivo may explain the failure of effector cell generation during progressive tumor growth. Taken together, these results demonstrate that the anti-CD3/IL-2 activation defines an immune response distinct from many previously described mechanisms of antitumor immune responses.

¹ This work was supported by USPHS Grant CA-49231 from the National Cancer Institute and by a grant from the Boston Foundation.

² Present address: Department of Medicine (II), Niigata University School of Medicine, Niigata City, Japan.

³ To whom requests for reprints should be addressed, at Oncology Laboratory, Department of Surgery, 1520 MSRB I, Box 0666, University of Michigan, Ann Arbor, MI 48109-0666.

Received 8/ 2/91. Accepted 12/13/91.

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