1. Department of Molecular Immunology and CREST program of JST, and,
2. Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
3. Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
4. Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
5. Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamada-oka, Suita, Osaka 565-0871, Japan
6. Biogen-Idec Inc, 12 Cambridge Center, Cambridge, Massachusetts 01746, USA
7. Howard Hughes Medical Institute and The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA

Correspondence to: Atsushi Kumanogoh^1,2Hitoshi Kikutani¹ Correspondence and requests for materials should be addressed to A.K. (Email: kumanogo@ragtime.biken.osaka-u.ac.jp) or H.K. (Email: kikutani@ragtime.biken.osaka-u.ac.jp).

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 1-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 11 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 11 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.

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