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Dual immunoregulatory pathways of 4-1BB signaling

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Abstract

It is perhaps rare to encounter among the various immunologically competent receptor–ligand pairs that a single cell surface determinant unleashes both a hidden suppressive function and costimulation. 4-1BB, an activation-induced tumor necrosis factor receptor family member chiefly viewed as a powerful T-cell costimulatory molecule, is one such example. Accumulated evidence in recent years uncovered an unknown facet of in vivo 4-1BB signaling (i.e., “active suppression”). Although in vitro signaling via 4-1BB is shown to support both CD4+ and CD8+ T-cell responses, the same induces a predominant CD8+ T-cell response suppressing CD4+ T-cell function when applied in vivo. How, when, and why such dual immunoregulatory effect of anti-4-1BB monoclonal antibody (MAB) comes into play is currently the focus of intense research. Existing data, although not complete, uncover several important aspects of in vivo 4-1BB signaling in the amelioration or exacerbation of various immune disorders. Despite minor disagreements, a majority agree that upregulation of interferon (IFN)-γ is critical to anti-4-1BB MAB therapy in addition to immune modulators such as interleukin 2, transforming growth factor β, and indolamine 2,3-dioxygenase5, all of which contribute greatly to the success of anti-4-1BB MAB-based immunotherapy. Anti-4-1BB MAB-mediated expansion of novel CD11c+CD8+ T cells is additional weaponry that appears critical for its in vivo suppressive function. These CD11c+CD8+ T cells express high levels of IFN-γ, become effective killers, and mediate selective suppression of CD4+ T cells. In this review, we discuss the dual nature (costimulatory and suppressive) of 4-1BB-mediated immune regulation, its current status, future direction, and its impact on the immune system, with special reference to its immunotherapy.

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Abbreviations

IDO:

indoleamine 2,3-dioxygenase

HSV-1:

herpes simplex virus type 1

TCR:

T-cell receptor

APC:

antigen-presenting cell

ConA:

concanavalin A

PHA:

phytohemagglutinin

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Acknowledgements

This work was supported in part by US Public Health Service grants RO1EY013325 (B.S.K.), KRF-2005-201-E00008, and KRF-2005-084-E00001; Korea Health 21 R&D, A050260; International Collaboration Fund, 2005-0441; and SRC funds to the IRC, University of Ulsan, Korea, from Korea Science and Engineering Foundation and the Korean Ministry of Science and Technology.

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  1. LSU Eye Center, Louisiana State University Health Sciences Center School of Medicine, Suite B, 2020 Gravier Street, New Orleans, LA, 70112, USA

    Dass S. Vinay & Byoung S. Kwon

  2. Immunomodulation Research Center and Department of Biological Sciences, University of Ulsan, Ulsan, Korea

    Kiweon Cha & Byoung S. Kwon

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  1. Dass S. Vinay
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Correspondence to Byoung S. Kwon.

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Vinay, D.S., Cha, K. & Kwon, B.S. Dual immunoregulatory pathways of 4-1BB signaling. J Mol Med 84, 726–736 (2006). https://doi.org/10.1007/s00109-006-0072-2

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