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

Nature volume 446, pages 680–684 (2007)Cite this article

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.

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Figure 1: α1β1 integrin is the functional receptor for Sema7A.
Figure 2: The mechanisms by which Sema7A stimulates monocytes and macrophages.
Figure 3: T-cell function and T-cell-mediated immunity in Sema7a -/- mice.
Figure 4: Involvement of Sema7A in the effector phase of the immune response.

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Acknowledgements

We thank K. Kubota for secretarial assistance. We are grateful to R. Hanayama, T. Toyofuku, T. Yasui and J. Encinas for critical advice, discussion and encouragement. We also thank T. Sugimoto, K. Shiozaki, I. Sizing and G. Majeau for technical support. This study was supported by the following funding agencies: the Ministry of Education, Culture, Sports, Science and Technology, Japan and CREST programme of JST (A.K. and H.K.); the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (A.K.); NINDS/NIH (A.L.K.); The Netherlands Organization for Scientific Research, The Human Frontier Science Program Organization and National Alliance for Research on Schizophrenia and Depression (R.J.P.); and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (K.S. and M.Y.). A.L.K. is an investigator of the Howard Hughes Medical Institute.

Author Contributions K.S. performed the main experimental work, analysed the results and wrote the manuscript. T.O., M.Y., N.T., H.T. and T.K. also performed experimental work. R.J.P. and A.L.K. produced Sema7a-/- mice. J.T. produced recombinant integrins. P.D.R. was involved in the study using Itga1-/- mice. A.K. and H.K. co-organized and performed project planning, data analysis and writing the manuscript

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Authors and Affiliations

  1. Department of Molecular Immunology and CREST program of JST, and,

    Kazuhiro Suzuki, Midori Yamamoto, Hyota Takamatsu, Atsushi Kumanogoh & Hitoshi Kikutani

  2. Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Noriko Takegahara & Atsushi Kumanogoh

  3. Department of Neurology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Tatsusada Okuno

  4. Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands,

    R. Jeroen Pasterkamp

  5. Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, 3-2 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Tomoe Kitao & Junichi Takagi

  6. Biogen-Idec Inc, 12 Cambridge Center, Cambridge, Massachusetts 01746, USA,

    Paul D. Rennert

  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,

    Alex L. Kolodkin

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  1. Kazuhiro Suzuki
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Correspondence to Atsushi Kumanogoh or Hitoshi Kikutani.

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Supplementary information

TITLE

This file contains Supplementary Methods with 19 additional references, and Supplementary Figures 1-13 with Legends summarized as follows: Supplementary Figure 1, Sema7A-induced cytokine production in monocytes and macrophages; Supplementary Figure 2, RGD-dependency of Sema7A-mediated cell adhesion; Supplementary Figure 3, impaired Sema7A-induced adhesion in Itga1-/- macrophages; Supplementary Figure 4, direct interaction between Sema7A and α1β1 integrin; Supplementary Figure 5, expression profiles of Sema7A on immune cells; Supplementary Figure 6, kinetics of Sema7A expression on T cells; Supplementary Figure 7, surface distribution of Sema7A and α1β1 integrin in unconjugated T cells and macrophages; Supplementary Figure 8, T cell-macrophage co-cultures in various settings; Supplementary Figure 9, histopathological examination in CHS and EAE; Supplementary Figure 10, T cell infiltrations in a passive EAE experiment; Supplementary Figure 11, passive EAE induced in Itga1-/- mice; Supplementary Figure 12, dose titration of MOG peptide in inducing EAE; Supplementary Figure 13, a model for the interaction of α1β1 integrin with Sema7A and collagens. (PDF 1398 kb)

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Suzuki, K., Okuno, T., Yamamoto, M. et al. Semaphorin 7A initiates T-cell-mediated inflammatory responses through α1β1 integrin. Nature 446, 680–684 (2007). https://doi.org/10.1038/nature05652

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