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Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M.L., Bianchi, R., Fioretti, M.C. and Puccetti, P. (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology, 3, 1097-1101. doi:10.1038/ni846

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• TITLE: Macrophage PD-L1 strikes back: PD-1/PD-L1 interaction drives macrophages toward regulatory subsets

  AUTHORS: Yun-Jung Lee, Young-Hye Moon, Kyeong Eun Hyung, Jong-Sun Yoo, Mi Ji Lee, Ik Hee Lee, Byung Sung Go, Kwang Woo Hwang

  KEYWORDS: Regulatory Macrophage; PD-1; PD-L1

  JOURNAL NAME: Advances in Bioscience and Biotechnology, Vol.4 No.8C, August 19, 2013

  ABSTRACT: Activated macrophages have been simply de?ned as cells that secrete in?ammatory mediators and kill intracellular pathogens until few years ago. Recent studies have proposed a new classification system to separate activated macrophages based on their functional phenotypes: host defense, wound healing, and immune regulation. Regulatory macrophages can arise following innate or adaptive immune responses and hinder macrophage-mediated host defense and inflammatory functions by inhibiting the production of pro-inflammatory mediators. In this study, we investigated whether PD-1 and PD-L1 interaction between macrophages and T cells alters macrophage activities. Our data provide evidence for PD-1/PD-L1 engagement inducing a regulatory profile in macrophages. Regulatory macrophages derived from PD-L1 signaling lost their host defense activity, which consists of the production of pro-inflammatory cytokine IL-6 and the exhibition of increased IL-10, SPHK1 and LIGHT gene levels in early phases of LPS stimulation. This differentiation seems to occur through excessive activation of TLR4 downstream MAPK signaling pathways. Regulatory macrophages induced from PD-1/PD-L1 interaction decrease inflammatory mediators and produce anti-inflammatory cytokines, so this macrophage subset has been under considerable attention as a possible immune regulation mechanism. Understanding and modulating regulatory macrophages may lead to new approches to treat or prevent auto-immune diseases such as type I diabetes, rheumatic syndrome and hypersensitivity-related diseases, which are concerned with the overproduction of inflammatory cytokines in macroages.