Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Nakatsuji, Yuji; Okuno, Tatsusada; Moriya, M.; Sugimoto, Tomoyuki; Kinoshita, Makoto; Takamatsu, Hyota; Nojima, Satoshi; Kimura, Tetsuya; Kang, Sujin; Ito, Daisuke; Nakagawa, Yukinobu; Toyofuku, Toshihiko; Takata, Ken; Nakano, Miki; Kubo, Masato; Suzuki, Sinobu; Matsui-Hasumi, Akiko; Uto-Konomi, Ayako; Ogata, Atsushi; Mochizuki, Hideki; Sakoda, Saburo; Kumanogoh, Atsushi

doi:10.4049/jimmunol.1102023

Cited by 65 publications

(82 citation statements)

References 50 publications

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“…SEMA4A, a class IV transmembrane semaphorin, is preferentially expressed in dendritic cells (DCs) and Th1 cells (25,26). We have previously demonstrated that SEMA4A is crucially involved not only in Ag-specific T cell priming, but also in Th1 cell and Th17 cell differentiation (26,27). In addition, SEMA4A is required for the function and stability of regulatory T (Treg) cells (28).…”

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confidence: 99%

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

Ito

Nojima

Nishide

et al. 2015

The Journal of Immunology

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Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4+ T cell responses, the involvement of mTOR in CD8+ T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8+ T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A−/− CD8+ T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8+ T cell responses were significantly impaired in SEMA4A−/− mice. Furthermore, SEMA4A−/− CD8+ T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8+ T cells. IFN-γ production and mTORC1 activity in SEMA4A−/− CD8+ T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8+ T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8+ T cells, but also reveal a novel link between a semaphorin and mTOR signaling.

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confidence: 99%

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

Ito

Nojima

Nishide

et al. 2015

The Journal of Immunology

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“…However, Sema4A have no influence on the effector phase of the disease course, as the mdel mice developed MS after MOG-specific CD4 + T cells are transferred even with the Sema4A antibody. Thus, Sema4A plays an important role in the development of EAE in the priming phase rather than the effector phase 19 . In patients with MS, serum Sema4A levels are markedly higher than in healthy control subjects or patients with other neurological diseases 19 .…”

Section: Sema4a and Immune Responsesmentioning

confidence: 99%

“…Thus, Sema4A plays an important role in the development of EAE in the priming phase rather than the effector phase 19 . In patients with MS, serum Sema4A levels are markedly higher than in healthy control subjects or patients with other neurological diseases 19 . While monocytes and DCs derived from healthy control subjects express moderate amounts of Sema4A, its expression levels are significantly higher in MS patients.…”

Section: Sema4a and Immune Responsesmentioning

confidence: 99%

“…While monocytes and DCs derived from healthy control subjects express moderate amounts of Sema4A, its expression levels are significantly higher in MS patients. The release of Sema4A can be prevented by inhibitors of proteases, including matrix metalloproteinases (MMPs) and ADAM metalloproteinases, suggesting that these enzymes play important roles in releasing Sema4A from the cell surface 19 . Moreover, mRNA expression of MMPs and ADAM 10 is higher in peripheral blood mononuclear cells (PBMCs) from MS patients with high serum concentrations of Sema4A than in those from healthy controls or MS patients with lower serum Sema4A levels.…”

Section: Sema4a and Immune Responsesmentioning

confidence: 99%

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The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems

Ito¹,

Kumanogoh²

2016

Cell Adhesion & Migration

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Semaphorins were originally identified as axon guidance cues that regulate the functional activity of axons in the nervous system. In addition, accumulating evidence indicates that semaphorins have multiple functions in physiological and pathogenic processes, including vascular development, tumor progression, and immune responses. Sema4A is a semaphorin expressed in immune cells, and is thus termed an “immune semaphorin.” Sema4A has 4 types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1. Recent studies suggest that Sema4A plays critical roles in many processes including cell–cell interactions, immune-cell activation, differentiation, and migration. In other studies, Sema4A is also associated with carcinogenesis and retinal systems. In this review, we summarize current knowledge regarding the biology of Sema4A in relation to angiogenesis, immune responses, colorectal cancer, and the retina.

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“…DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment 14) . In Japan, we have a free support system for measuring Sema4A to predict the responsiveness of IFNs at Osaka University.…”

Section: ) Ifnsmentioning

confidence: 99%

The Current State of Immune Therapy in Multiple Sclerosis in Japan and Future Prospects

Yokoyama

2015

Juntendo Medical Journal

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Among neuroimmunological disorders, the most common disease is multiple sclerosis (MS). MS is an intractable disease particularly affecting young adults and is increasing all over the world, including Japan. The main goal of treatment is to decrease the frequency of relapses, manage symptoms, improve function, and delay disease progression for good quality of life. To prevent relapses, interferon beta 1b, an injectable disease-modifying therapy (DMT), has been used; however, it has been only available in Japan since 2000, about seven years behind world usage, because of the drug lag caused by healthcare system barriers. At present, second-line DMTs, such as fingolimod and natalizumab, are available; both are more effective compared to first-line injectable interferons and glatiramer acetate (approved on September 28, 2015). However, it is still difficult to block the neurodegenerative process of axonal damage, and that is why there is no cure for MS. In this article, we summarize current immunotherapy in Japan and discuss the pros and cons of the newer DMTs, which might modulate disease course.We also discuss the future prospects of DMTs. Even if DMT treatment is initiated immediately after the completion of diagnosis, patients need to remain on therapy for a long period of time. Adhering patients to treatment is another important aspect. In this regard, a treatment algorithm for escalation therapy or early aggressive induction therapy is not a final decision, and we need to reconsider other better options with low risk of drug adverse effect, and exclude pregnancy-related risks in females.

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Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Cited by 65 publications

References 50 publications

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems

The Current State of Immune Therapy in Multiple Sclerosis in Japan and Future Prospects

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