The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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© The Rockefeller University Press, 0022-1007/2000/1/375/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 375-380

Brief Definitive Report

Critical Contribution of OX40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis

Hisaya Akibaa,c, Yasushi Miyahirab, Machiko Atsutaa,c, Kazuyoshi Takedaa,c, Chiyoko Noharaa, Toshiro Futagawaa, Hironori Matsudaa, Takashi Aokib, Hideo Yagitaa,c, and Ko Okumuraa,c
a Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
b Department of Parasitology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
c CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation, Tokyo 101-0062, Japan

Correspondence to: Hideo Yagita, Dept. of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel:81-3-3818-9284 Fax:81-3-3813-0421 E-mail:hyagita{at}med.juntendo.ac.jp.

Infection of inbred mouse strains with Leishmania major is a well characterized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfamily, in the development of Th1 and Th2 cells in vivo, we administered monoclonal antibody (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti–4-1BBL mAb exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4+ T cells and OX40L was expressed on CD11c+ dendritic cells in the popliteal lymph nodes of L. major–infected BALB/c mice. In vitro stimulation of these CD4+ T cells showed that anti-OX40L mAb treatment resulted in substantially reduced production of Th2 cytokines. Moreover, this change in cytokine levels was associated with reduced levels of anti–L. major immunoglobulin (Ig)G1 and serum IgE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppressing the development of Th2 responses, substantiating a critical role of OX40–OX40L interaction in Th2 development in vivo.

Key Words: OX40/OX40 ligand, experimental leishmaniasis, Th1/Th2 differentiation, costimulation, TNF/TNF receptor family


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