Semaphorin 7A initiates T-cell-mediated inflammatory responses through α1β1 integrin

Kazuhiro Suzuki, Tatsusada Okuno, Midori Yamamoto, R. Jeroen Pasterkamp, Noriko Takegahara, Hyota Takamatsu, Tomoe Kitao, Junichi Takagi, Paul D. Rennert, Alex L. Kolodkin, Atsushi Kumanogoh () and Hitoshi Kikutani ()
Additional contact information
Kazuhiro Suzuki: and
Tatsusada Okuno: Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
Midori Yamamoto: and
R. Jeroen Pasterkamp: Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Noriko Takegahara: Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
Hyota Takamatsu: and
Tomoe Kitao: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamada-oka, Suita, Osaka 565-0871, Japan
Junichi Takagi: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamada-oka, Suita, Osaka 565-0871, Japan
Paul D. Rennert: Biogen-Idec Inc, 12 Cambridge Center, Cambridge, Massachusetts 01746, USA
Alex L. Kolodkin: The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA
Atsushi Kumanogoh: and
Hitoshi Kikutani: and

Nature, 2007, vol. 446, issue 7136, 680-684

Abstract: Abstract Semaphorins are axon guidance factors that assist growing axons in finding appropriate targets and forming synapses1. Emerging evidence suggests that semaphorins are involved not only in embryonic development but also in immune responses2. Semaphorin 7A (Sema7A; also known as CD108)3,4, which is a glycosylphosphatidylinositol-anchored semaphorin, promotes axon outgrowth through β1-integrin receptors and contributes to the formation of the lateral olfactory tract5. Although Sema7A has been shown to stimulate human monocytes6, its function as a negative regulator of T-cell responses has also been reported7. Thus, the precise function of Sema7A in the immune system remains unclear. Here we show that Sema7A, which is expressed on activated T cells, stimulates cytokine production in monocytes and macrophages through α1β1 integrin (also known as very late antigen-1) as a component of the immunological synapse, and is critical for the effector phase of the inflammatory immune response. Sema7A-deficient (Sema7a-/-) mice are defective in cell-mediated immune responses such as contact hypersensitivity and experimental autoimmune encephalomyelitis. Although antigen-specific and cytokine-producing effector T cells can develop and migrate into antigen-challenged sites in Sema7a-/- mice, Sema7a-/- T cells fail to induce contact hypersensitivity even when directly injected into the antigen-challenged sites. Thus, the interaction between Sema7A and α1β1 integrin is crucial at the site of inflammation. These findings not only identify a function of Sema7A as an effector molecule in T-cell-mediated inflammation, but also reveal a mechanism of integrin-mediated immune regulation.

Date: 2007
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DOI: 10.1038/nature05652

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