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PMID:17377534

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Citation

Suzuki, K, Okuno, T, Yamamoto, M, Pasterkamp, RJ, Takegahara, N, Takamatsu, H, Kitao, T, Takagi, J, Rennert, PD, Kolodkin, AL, Kumanogoh, A and Kikutani, H (2007) Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. Nature 446:680-4

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.

Links

PubMed Online version:10.1038/nature05652

Keywords

Animals; Antigens, CD/genetics; Antigens, CD/metabolism; Cytokines/secretion; Immunity/immunology; Inflammation/immunology; Integrin alpha1beta1/metabolism; Macrophage Activation; Macrophages/immunology; Macrophages/metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes/immunology; Monocytes/metabolism; Semaphorins/deficiency; Semaphorins/genetics; Semaphorins/metabolism; Signal Transduction; T-Lymphocytes/immunology; T-Lymphocytes/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ITB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9QUR8

F

Seeded From UniProt

complete

MOUSE:ITA1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9QUR8

F

Seeded From UniProt

complete

MOUSE:SEM7A

enables

GO:0005178: integrin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P09055

F

Seeded From UniProt

complete

MOUSE:SEM7A

enables

GO:0005178: integrin binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q3V3R4

F

Seeded From UniProt

complete

MOUSE:SEM7A

located_in

GO:0009897: external side of plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SEM7A

involved_in

GO:0007229: integrin-mediated signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SEM7A

involved_in

GO:0050727: regulation of inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SEM7A

involved_in

GO:0060907: positive regulation of macrophage cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SEM7A

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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