Activating Receptor NKG2D Targets RAE-1-Expressing Allogeneic Neural Precursor Cells in a Viral Model of Multiple Sclerosis

Authors

  • Jason G. Weinger,

    1. Department of Molecular Biology & Biochemistry
    2. Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, USA
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  • Warren C. Plaisted,

    1. Department of Molecular Biology & Biochemistry
    2. Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, USA
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  • Sonia M. Maciejewski,

    1. Department of Molecular Biology & Biochemistry
    2. Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, USA
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  • Lewis L. Lanier,

    1. Department of Microbiology & Immunology and the Cancer Research Institute, University of California, San Francisco, California
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  • Craig M. Walsh,

    1. Department of Molecular Biology & Biochemistry
    2. Multiple Sclerosis Research Center, University of California, Irvine, California, USA
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  • Thomas E. Lane

    Corresponding author
    1. Department of Molecular Biology & Biochemistry
    2. Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, USA
    3. Multiple Sclerosis Research Center, University of California, Irvine, California, USA
    • Correspondence: Thomas E. Lane, Ph.D., Department of Pathology, Division of Microbiology & Immunology, University of Utah, School of Medicine, Salt Lake City, Utah 84112, USA. Telephone: 801-585-5554; Fax: 801-585-2417; e-mail: tom.lane@path.utah.edu

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  • Author contributions: J.G.W.: designed experiments, collected data for analysis and interpretation, and wrote the manuscript; W.C.P. and S.M.M.: collected data for analysis and interpretation; C.M.W.: provided financial support; L.L.L.: provided study material and assisted in manuscript writing; T.E.L.: designed experiments, analyzed and interpreted data, provided financial support, and wrote the manuscript.

Abstract

Transplantation of major histocompatibility complex-mismatched mouse neural precursor cells (NPCs) into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in rapid rejection that is mediated, in part, by T cells. However, the contribution of the innate immune response to allograft rejection in a model of viral-induced neurological disease has not been well defined. Herein, we demonstrate that the natural killer (NK) cell-expressing-activating receptor NKG2D participates in transplanted allogeneic NPC rejection in mice persistently infected with JHMV. Cultured NPCs derived from C57BL/6 (H-2b) mice express the NKG2D ligand retinoic acid early precursor transcript (RAE)-1 but expression was dramatically reduced upon differentiation into either glia or neurons. RAE-1+ NPCs were susceptible to NK cell-mediated killing whereas RAE-1 cells were resistant to lysis. Transplantation of C57BL/6-derived NPCs into JHMV-infected BALB/c (H-2d) mice resulted in infiltration of NKG2D+CD49b+ NK cells and treatment with blocking antibody specific for NKG2D increased survival of allogeneic NPCs. Furthermore, transplantation of differentiated RAE-1 allogeneic NPCs into JHMV-infected BALB/c mice resulted in enhanced survival, highlighting a role for the NKG2D/RAE-1 signaling axis in allograft rejection. We also demonstrate that transplantation of allogeneic NPCs into JHMV-infected mice resulted in infection of the transplanted cells suggesting that these cells may be targets for infection. Viral infection of cultured cells increased RAE-1 expression, resulting in enhanced NK cell-mediated killing through NKG2D recognition. Collectively, these results show that in a viral-induced demyelination model, NK cells contribute to rejection of allogeneic NPCs through an NKG2D signaling pathway. Stem Cells 2014;32:2690–2701

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