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Induction of Tumor Regression by Administration of B7-Ig Fusion Proteins: Mediation by Type 2 CD8⁺ T Cells and Dependence on IL-4 Production¹

Nobuya Yamaguchi^*, Shin-ichiro Hiraoka^*, Takao Mukai^*, Noritami Takeuchi^*, Xu-Yu Zhou^*, Shiro Ono^*, Mikihiko Kogo, Kyriaki Dunussi-Joannopoulos, Vincent Ling, Stanley Wolf and Hiromi Fujiwara^2,*

^* Department of Oncology, Osaka University Graduate School of Medicine, Yamada-oka, Suita, Osaka 565-0871, Japan; First Department of Oral and Maxillo-Facial Surgery, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan; and Department of Inflammation, Wyeth/Research Institute, Cambridge, MA 02140

CD28 signals contribute to either type 1 or type 2 T cell differentiation. Here, we show that administration of B7.2-Ig fusion proteins to tumor-bearing mice induces tumor regression by promoting the differentiation of antitumor type 2 CD8⁺ effector T cells along with IL-4 production. B7.2-Ig-mediated regression was not induced in IL-4^-/- and STAT6^-/- mice. However, it was elicited in IFN-^-/- and STAT4^-/- mice. By contrast, IL-12-induced tumor regression occurred in IL-4^-/- and STAT6^-/- mice, but not in IFN-^-/- and STAT4^-/- mice. Moreover, B7.2-Ig treatment was effective in a tumor model not responsive to IL-12. B7.2-Ig administration elicited elevated levels of IL-4 production. Tumor regression was predominantly mediated by CD8⁺ T cells, although the induction of these effector cells required CD4⁺ T cells. Tumor regression induced by CD8⁺ T cells alone was inhibited by neutralizing the IL-4 produced during B7.2-Ig treatment. Thus, these results indicate that stimulation in vivo of CD28 with B7.2-Ig in tumor-bearing mice results in enhanced induction of antitumor type 2 CD8⁺ T cells (Tc2) leading to Tc2-mediated tumor regression.

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