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International Immunology Advance Access published online on January 21, 2008
International Immunology, doi:10.1093/intimm/dxn006
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Plexin-A4 negatively regulates T lymphocyte responses

Midori Yamamoto1, Kazuhiro Suzuki1, Tatsusada Okuno2, Takehiro Ogata1, Noriko Takegahara2, Hyota Takamatsu2, Masayuki Mizui1, Masahiko Taniguchi3, Alain Chédotal4, Fumikazu Suto5, Hajime Fujisawa6, Atsushi Kumanogoh2,7 and Hitoshi Kikutani1,7

1 Department of Molecular Immunology and Core Research for Evolutional Science and Technology program of the Japan Science and Technology Agency and
2 Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
3 Department of Biochemistry, Cancer Research Institute, Sapporo Medical University School of Medicine, S-1, W-17, Chuo-ku, Sapporo 060-8556, Japan
4 Central National de la Recherche Scientifique, Unité Mixte de la Recherche 7102, Université Paris 6, Batiment B, piéce 603, Case12, 9 Quai Saint Bernard, 75005 Paris, France
5 Division of Developmental Genetics, National Institute of Genetics, Mishima 411-8450, Japan
6 Division of Biological Science, Nagoya University Graduated School of Science, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
7 World Premier International Immunology Frontier Research Center, Osaka University, Yamada-oka, Suita, Osaka 565-0871, Japan

Correspondence to: Correspondence to: A. Kumanogoh; E-mail: kumanogo{at}ragtime.biken.osaka-u.ac.jp and H. Kikutani; E-mail: kikutani{at}ragtime.biken.osaka-u.ac.jp

Semaphorins and their receptors play crucial roles not only in axon guidance during neuronal development but also in the regulation of immune responses. Plexin-A4, a member of the plexin-A subfamily, forms a receptor complex with neuropilins and transduces signals for class III semaphorins in the nervous system. Although plexin-A4 is also expressed in the lymphoid tissues, the involvement of plexin-A4 in immune responses remains unknown. To explore the role of plexin-A4 in the immune system, we analyzed immune responses in plexin-A4-deficient (plexin-A4–/–) mice. Among immune cells, plexin-A4 mRNA was detected in T cells, dendritic cells and macrophages but not in B cells and NK cells. Plexin-A4–/– mice had normal numbers and cell surface markers for each lymphocyte subset, suggesting that plexin-A4 is not essential for lymphocyte development. However, plexin-A4–/– mice exhibited enhanced antigen-specific T cell responses and heightened sensitivity to experimental autoimmune encephalomyelitis. Plexin-A4–/– T cells exhibited hyperproliferative responses to anti-CD3 stimulation and to allogeneic dendritic cells in vitro. Furthermore, this hyperproliferation was also observed in both T cells from neuropilin-1 mutant (npn-1Sema–) mice, in which the binding site of class III semaphorins is disrupted, and T cells from Sema3A-deficient (Sema-3A–/–) mice. Collectively, these results suggest that plexin-A4, as a component of the receptor complex for class III semaphorins, negatively regulates T cell-mediated immune responses.

Keywords: EAE, hyperresponse, plexin, semaphorin, T cell

Received 17 December 2007, accepted 3 January 2008.


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