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

Regulation of immune cell responses by semaphorins and their receptors

“…28 Recombinant Sema7A protein stimulates monocytes/macrophages through a1b1 integrin, inducing proinflammatory cytokine production. 27 Furthermore, Sema7A receptor usage in the immune system is consistent with that in olfactory nerve outgrowth. 28 Sema7A is also involved in pathogenic immune responses.…”

“…For example, Sema3E signals independently of NPs through plexin-D1, 16 while Sema7A uses integrins to exert its functions in both the nervous and immune systems. 27,28 In addition, two molecules unrelated to plexins and NPs, CD72 29 and T-cell immunoglobulin and mucin domaincontaining protein 2 (TIM-2), 30 functionally interact with Sema4D and Sema4A, respectively, in the immune system (Figure 1).…”

“…63 In the immune system, Sema7A is induced on activated T cells. 27 Sema7A contains an arginine-glycineaspartate in its Sema domain that is a well-conserved integrin-binding motif. 28 Recombinant Sema7A protein stimulates monocytes/macrophages through a1b1 integrin, inducing proinflammatory cytokine production.…”

“…Sema7A-deficient mice are resistant to inflammation, including hapten-induced contact hypersensitivity and EAE. 27 In addition, Sema7A plays an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis by regulating transforming growth factor-b signaling. 64 NP-1: a class III semaphorin and vascular endothelial growth factor receptor that is necessary to regulate immune responses and tumor angiogenesis As described above, NP-1 was originally identified as a cell surface glycoprotein that functions as a class III semaphorin receptor.…”

“…86,88 In addition, Sema7A, which can stimulate monocytes/macrophages to produce inflammatory cytokines through a1b1 integrin, 27 has been suggested to function as an attractant for human monocytes. 89 Furthermore, a viral semaphorin, A39R, which is a ligand for plexin-C1, inhibits DC integrin-mediated adhesion and chemokine (CCL3)-induced migration through actin cytoskeletal rearrangement.…”