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C. Stremmel^*, E.A. Greenfield^*,, E. Howard^*, G.J. Freeman, and V.K. Kuchroo^*

From the ^* Center for Neurological Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115; and the Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

For T cells to become functionally activated they require at least two signals. The B7 costimulatory molecules B7-1 and B7-2 provide the "second signal" pivotal for T cell activation. In this report, we studied the relative roles of B7-1 and B7-2 molecules in the induction of antitumor immunity to the T cell thymoma, EL4. We generated EL4 tumor cells that expressed B7-1, B7-2, and B7-1+B7-2 by transfecting murine cDNAs. Our results demonstrate that EL4–B7-1 cells are completely rejected in syngeneic mice. Unlike EL4–B7-1 cells, we find that EL4–B7-2 cells are not rejected but progressively grow in the mice. A B7-1– and B7-2–EL4 double transfectant was generated by introducing B7-2 cDNA into the EL4–B7-1 tumor line that regressed in vivo. The EL4–B7-1+B7-2 double transfectant was not rejected when implanted into syngeneic mice but progressively grew to produce tumors. The double transfectant EL4 cells could costimulate T cell proliferation that could be blocked by anti–B7-1 antibodies, anti–B7-2 antibodies, or hCTLA4 immunoglobulin, showing that the B7-1 and B7-2 molecules expressed on the EL4 cells were functional. In vivo, treatment of mice implanted with double-transfected EL4 cells with anti–B7-2 monoclonal antibody resulted in tumor rejection. Furthermore, the EL4–B7-2 and EL4–B7-1+B7-2 cells, but not the wild-type EL4 cells, were rejected in interleukin 4 (IL-4) knockout mice. Our data suggests that B7-2 expressed on some T cell tumors inhibits development of antitumor immunity, and IL-4 appears to play a critical role in abrogation of the antitumor immune response.

Key Words: T lymphoma • B7-2 • immune suppression • interleukin 4 • interleukin 10

C. Stremmel was supported by a research scholarship from the German Research Association (STR 544/1). This work was supported by grants from the National Institutes of Health (RO1 NS-35685, RO1 AI-39671-01AI, CA AI 75174, and AI 25082) and the National Multiple Sclerosis Society (RG 2571 and RG 2320).

Abbreviations used: wt, wild-type.

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