Full-length Article AMIGO2 modulates T cell functions and its deficiency in mice ameliorates experimental autoimmune encephalomyelitis Zhilin Li a , Mohd Moin Khan b , Juha Kuja-Panula a , Hongyun Wang c , Yu Chen c , Deyin Guo c,d , Zhi Jane Chen b , Riitta Lahesmaa b , Heikki Rauvala a , Li Tian a,e,⇑ a Neuroscience Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland b Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland c College of Life Sciences, Wuhan University, Wuhan, China d School of Basic Medical Sciences, Wuhan University, Wuhan, China e Psychiatry Research Center, Beijing Huilongguan Hospital, Peking University, Beijing, China article info Article history: Received 27 July 2016 Received in revised form 26 December 2016 Accepted 10 January 2017 Available online 1 February 2017 Keywords: AMIGO2 EAE MS T-bet GATA-3 Akt NF-kB NFAT1 GSK-3b abstract The immune function of AMIGO2 is currently unknown. Here, we revealed novel roles of AMIGO2 in mod- ulating T-cell functions and EAE using Amigo2-knockout (AMG2KO) mice. Amigo2 was abundantly expressed by murine T helper (Th) cells. Its deficiency impaired transplanted T-cell infiltration into the secondary lymphoid organs and dampened Th-cell activation, but promoted splenic Th-cell proliferation and abundancy therein. AMG2KO Th cells had respectively elevated T-bet in Th1- and GATA-3 in Th2- lineage during early Th-cell differentiation, accompanied with increased IFN-c and IL-10 but decreased IL-17A production. AMG2KO mice exhibited ameliorated EAE, dampened spinal T-cell accumulation, decreased serum IL-17A levels and enhanced splenic IL-10 production. Adoptive transfer of encephalito- genic AMG2KO T cells induced milder EAE and dampened spinal Th-cell accumulation and Tnf expression. Mechanistically, Amigo2-overexpression in 293T cells dampened NF-kB transcriptional activity, while Amigo2-deficiency enhanced Akt but suppressed GSK-3b phosphorylation and promoted nuclear translo- cations of NF-kB and NFAT1 in Th-cells. Collectively, our data demonstrate that AMIGO2 is important in regulating T-cell functions and EAE, and may be harnessed as a potential therapeutic target for multiple sclerosis. Ó 2017 Elsevier Inc. All rights reserved. 1. Introduction Amphoterin-induced gene and open reading frame (AMIGO) was transcriptionally induced in primary rat hippocampal neurons when being stimulated by neurite-promoting protein amphoterin (also known as high motility group box 1) (Kuja-Panula et al., 2003). Together with two other gene homologues Amigo2 and Amigo3, they constitute a novel family of type I transmembrane proteins, which contain six leucine-rich repeats and one immunoglobulin-like domain in the extracellular amino terminus. So far, most studies concerning AMIGO2 have focused on its neuronal functions. For example, AMIGO2 was shown to promote cerebellar granule neuronal survival and inhibit apoptosis, and may be involved in social memory formation and mental retarda- tion (Chen et al., 2012; Gimelli et al., 2011; Hitti and Siegelbaum, 2014; Miyake et al., 2004; Ono et al., 2003). However, scanty evi- dence has shown its involvement in the immune system. Our pre- vious study demonstrated that the mRNA expression of human AMIGO2 was significantly upregulated in Th2 cells as compared to Th0 and Th1 cells (Lund et al., 2007), thereby indicating a possi- ble involvement of AMIGO2 in Th cell differentiation. Regarding cell signaling, so far no ligands have been identified to signal through AMIGO2. Multiple sclerosis (MS) is the most common chronic inflamma- tory demyelinating disease of the human central nervous system (CNS) (Dendrou et al., 2015). A multitude of autoimmune mecha- nisms underlie the disease onset and progression of MS. Currently available immunomodulatory medications are not universally effective and there is an urgent need for a better understanding of contributing immune mechanisms to improve the efficacy and personalization of such medications. Therefore, it is imperative to http://dx.doi.org/10.1016/j.bbi.2017.01.009 0889-1591/Ó 2017 Elsevier Inc. All rights reserved. ⇑ Corresponding author at: Neuroscience Center, University of Helsinki, Viikin- kaari 4, FIN-00014 Helsinki, Finland. E-mail addresses: zhilin.li@helsinki.fi (Z. Li), mkhan@btk.fi (M.M. Khan), juha. kuja-panula@helsinki.fi (J. Kuja-Panula), 1328492097@qq.com (H. Wang), chenyu@whu.edu.cn (Y. Chen), dguo@whu.edu.cn (D. Guo), zchen@btk.fi (Z.J. Chen), riitta.lahesmaa@btk.fi (R. Lahesmaa), heikki.rauvala@helsinki.fi (H. Rauvala), li.tian@helsinki.fi (L. Tian). Brain, Behavior, and Immunity 62 (2017) 110–123 Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi