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  • Interestingly our analyses of human


    Interestingly, our analyses of human PBMCs using a monoclonal antibody against EBI2 showed that the expression pattern of human EBI2 is largely overlapping with that in mice. Especially Th17 HBTU showed homogeneous high expression of EBI2 compared with Th1 cells, which contained a fraction of cells negative for EBI2. Furthermore, when we analyzed histological sections of lesions from MS patients, we found expression of EBI2 restricted to mononuclear cells present within inflamed white matter regions. Most cells expressing EBI2 morphologically appeared as infiltrating macrophages. We found T cells that were clearly negative and T cells with strong expression of EBI2 in MS lesions. This finding is in accordance with our flow cytometry data showing that only a part of all T cells express EBI2 and the fact that MS lesions are known to be dominated by CD8 cells (Babbe et al., 2000), which are largely negative for EBI2. Because EBI2 is expressed on the major subsets of immune cells, and small molecule antagonists for EBI2 were recently described (Benned-Jensen et al., 2013, Gessier et al., 2014), EBI2 constitutes a tempting drug target reminiscent of the sphingosine-1-phosphate receptor superagonist fingolimod/Gilenya that is currently in clinical use for treatment of MS patients.
    Experimental Procedures Detailed descriptions about mass spectrometry, single cell RT-PCR, and immunohistochemistry are provided in the Supplemental Information.
    Author Contributions
    Acknowledgments We thank Petra Adams, Alexei Nikolaev, Marina Snetkova, and Elena Zurkowski for excellent technical assistance and Sebastian Attig (TRON, Mainz) and Alexander Hobhberger (FZI, Mainz) for cell sorting. This work was supported by the Deutsche Forschungsgemeinschaft SFB/TR-128 TPA3 to N.W. and F.C.K., TPA7 to A.W., TPZ1 to T.K., and by SFB/TR-156 TP C01 to F.C.K. and A.W. S.C. was supported by the Italian Association for Cancer Research (AIRC). A.W.S., I.C., and J.Z. are employees of Novartis Pharma, Basel, Switzerland and some of them hold stock and/or stock options in their company.
    Introduction Innate lymphoid cells (ILCs) are recently described immune cells of lymphoid origin and include cytotoxic natural killer (NK) cells and interleukin-7 receptor alpha (also known as CD127)+ subsets, which, similar to T helper (Th) lymphocytes, can be distinguished on the basis of signature transcription factors and effector cytokines: (1) ILC1s require the transcription factor T-BET and produce interferon-γ. (2) ILC2s express the transcription factor GATA3 and produce the type 2 cytokines interleukin 5 (IL-5) and IL-13. (3) ILC3s are dependent on the transcription factor RAR-related orphan receptor gamma t (RORγt) and have the ability to produce IL-17 and/or IL-22. ILC3s are enriched in the intestine, where they maintain healthy tissue function by orchestrating lymphoid-organ development, containment of commensal bacteria, tissue repair, host defense, and regulation of adaptive immunity (Artis and Spits, 2015, Diefenbach et al., 2014, Eberl et al., 2015, McKenzie et al., 2014, Serafini et al., 2015, Sonnenberg and Artis, 2015). ILC3s can be divided into two main populations with distinct ontogeny, transcriptional programs, and localization within the gut: (1) C-C motif chemokine receptor 6 (CCR6)− ILC3s co-expressing RORγt and T-BET are mainly found scattered throughout the lamina propria (Luci et al., 2009, Sanos et al., 2009, Satoh-Takayama et al., 2008). (2) CCR6+NKp46− fetal lymphoid tissue inducer (LTi) and adult LTi-like cells expressing c-KIT (also known as CD117) seed the gut during fetal development, develop along a pathway distinct from that of other ILCs, and promote lymphoid tissue development (Eberl and Littman, 2004, Eberl et al., 2004, Mebius et al., 1997, Sawa et al., 2010). Accordingly, LTi cells reside in intestinal lymphoid structures, called cryptopatches (CPs) (Kanamori et al., 1996) and isolated lymphoid follicles (ILFs) (Hamada et al., 2002), which are collectively referred to as solitary intestinal lymphoid tissues (SILTs) (Buettner and Lochner, 2016, Randall and Mebius, 2014). CPs are clusters of LTi-like ILC3s surrounded by dendritic cells (DCs) within a network of stromal cells, whereas ILFs additionally contain B cells. CPs and ILFs develop postnatally through the activity of adult LTi-like ILC3s that produce lymphotoxin (Eberl and Littman, 2004, Kruglov et al., 2013, Tsuji et al., 2008). Whereas lymphoid organogenesis in the small intestine has been well studied, the specific factors required for SILT development in the colon, beyond lymphotoxin, are unknown.