title: Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin.
abstract: Semaphorins are axon guidance factors that assist growing axons in finding appropriate targets and forming synapses. Emerging evidence suggests that semaphorins are involved not only in embryonic development but also in immune responses. Semaphorin 7A (Sema7A; also known as CD108), which is a glycosylphosphatidylinositol-anchored semaphorin, promotes axon outgrowth through beta1-integrin receptors and contributes to the formation of the lateral olfactory tract. Although Sema7A has been shown to stimulate human monocytes, its function as a negative regulator of T-cell responses has also been reported. 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 alpha1beta1 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 alpha1beta1 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.
authors: Department of Molecular Immunology and CREST program of JST, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors: Kazuhiro
authors: K
authors: Suzuki
authors: Tatsusada
authors: T
authors: Okuno
authors: Midori
authors: M
authors: Yamamoto
authors: R Jeroen
authors: RJ
authors: Pasterkamp
authors: Noriko
authors: N
authors: Takegahara
authors: Hyota
authors: H
authors: Takamatsu
authors: Tomoe
authors: T
authors: Kitao
authors: Junichi
authors: J
authors: Takagi
authors: Paul D
authors: PD
authors: Rennert
authors: Alex L
authors: AL
authors: Kolodkin
authors: Atsushi
authors: A
authors: Kumanogoh
authors: Hitoshi
authors: H
authors: Kikutani
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D007109:Immunity / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D039222:Integrin alpha1beta1 / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D039961:Semaphorins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D039222:Integrin alpha1beta1; C485571:Sema7a protein, mouse; D039961:Semaphorins