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CD28-Independent Costimulation of T Cells by OX40 Ligand and CD70 on Activated B Cells¹

Hisaya Akiba^*,, Hideo Oshima^*,, Kazuyoshi Takeda^*,, Machiko Atsuta^*,, Hiroyasu Nakano^*,, Atsuo Nakajima^§, Chiyoko Nohara^*, Hideo Yagita^*, and Ko Okumura^2,*,

^* Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation, Tokyo, Japan; Department of Surgery, Faculty of Medicine, University of Tokyo, Tokyo, Japan; and ^§ Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan

OX40 and its ligand (OX40L) have been implicated in T cell-dependent humoral immune responses. To further characterize the role of OX40/OX40L in T-B cell interaction, we newly generated an anti-mouse OX40L mAb (RM134L) that can inhibit the costimulatory activity of OX40L transfectants for anti-CD3-stimulated T cell proliferation. Flow cytometric analyses using RM134L and an anti-mouse OX40 mAb indicated that OX40 was inducible on splenic T cells by stimulation with immobilized anti-CD3 mAb in a CD28-independent manner, while OX40L was not expressed on resting or activated T cells. OX40L was inducible on splenic B cells by stimulation with anti-IgM Ab plus anti-CD40 mAb, but not by either alone. These activated B cells exhibited a potent costimulatory activity for anti-CD3-stimulated T cell proliferation and IL-2 production. Anti-CD80 and anti-CD86 mAbs partially inhibited the costimulatory activity, and further inhibition was obtained by their combination with RM134L and/or anti-CD70 mAb. We also found the anti-IgM Ab- plus anti-CD40 mAb-stimulated B cells exhibited a potent costimulatory activity for proliferation of and IL-2 production by anti-CD3-stimulated CD28^- T cells from CD28-deficient mice, which was substantially inhibited by RM134L and/or anti-CD70 mAb. These results indicated that OX40L and CD70 expressed on surface Ig- and CD40-stimulated B cells can provide CD28-independent costimulatory signals to T cells.