Natural killer cell-activating receptor NKG2D mediates innate immune targeting of allogeneic neural progenitor cell grafts

Authors

  • Lori K. Phillips,

    1. Program in Immunology Stanford University School of Medicine University of Colorado, Boulder, Colorado, USA
    Search for more papers by this author
  • Elizabeth A. Gould,

    1. Graduate Program in Neuroscience University of Colorado, Boulder, Colorado, USA
    2. Institute for Stem Cell Biology and Regenerative Medicine, Division of Transplantation, Stanford University School of Medicine, Stanford, California, USA
    Search for more papers by this author
  • Harish Babu,

    1. Institute for Stem Cell Biology and Regenerative Medicine, Division of Transplantation, Stanford University School of Medicine, Stanford, California, USA
    2. Department of Neurosurgery and Division of Transplantation, Stanford University School of Medicine, Stanford, California, USA
    Search for more papers by this author
  • Sheri M. Krams,

    1. Program in Immunology Stanford University School of Medicine University of Colorado, Boulder, Colorado, USA
    2. Department of Surgery Division of Transplantation, Stanford University School of Medicine, Stanford, California, USA
    Search for more papers by this author
  • Theo D. Palmer,

    Corresponding author
    1. Institute for Stem Cell Biology and Regenerative Medicine, Division of Transplantation, Stanford University School of Medicine, Stanford, California, USA
    • 1201 Welch Road, MSLS P301, Stanford, California 94305, USATheo D. Palmer, Ph.D., 265 Campus Drive, Lorry I Lokey Stem Cell Building, Room 1141, Stanford, California 94305, USA. E-mail: tpalmer@stanford.edu omm@stanford.edu Telephone: 650-498-6247; Fax: 650-498-6250

    Search for more papers by this author
  • Olivia M. Martinez

    Corresponding author
    1. Program in Immunology Stanford University School of Medicine University of Colorado, Boulder, Colorado, USA
    • 1201 Welch Road, MSLS P301, Stanford, California 94305, USATheo D. Palmer, Ph.D., 265 Campus Drive, Lorry I Lokey Stem Cell Building, Room 1141, Stanford, California 94305, USA. E-mail: tpalmer@stanford.edu omm@stanford.edu Telephone: 650-498-6247; Fax: 650-498-6250

    Search for more papers by this author

  • Author contributions: L.K.P.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; E.A.G.: collection and/or assembly of data; H.B.: collection and/or assembly of data, data analysis and interpretation, and provision of study material; S.M.K.: conception and design, data analysis and interpretation, and provision of study material; T.D.P.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, and final approval of manuscript; O.M.M.: conception and design, financial support, administrative support, data analysis and interpretation, manuscript writing, final approval of manuscript. *co-senior authors.

Abstract

Cell replacement therapy holds promise for a number of untreatable neurological or psychiatric diseases but the immunogenicity of cellular grafts remains controversial. Emerging stem cell and reprogramming technologies can be used to generate autologous grafts that minimize immunological concerns but autologous grafts may carry an underlying genetic vulnerability that reduces graft efficacy or survival. Healthy allogeneic grafts are an attractive and commercially scalable alternative if immunological variables can be controlled. Stem cells and immature neural progenitor cells (NPC) do not express major histocompatibility complex (MHC) antigens and can evade adaptive immune surveillance. Nevertheless, in an experimental murine model, allogeneic NPCs do not survive and differentiate as well as syngeneic grafts, even when traditional immunosuppressive treatments are used. In this study, we show that natural killer (NK) cells recognize the lack of self-MHC antigens on NPCs and pose a barrier to NPC transplantation. NK cells readily target both syngeneic and allogeneic NPC, and killing is modulated primarily by NK-inhibiting “self” class I MHC and NK-activating NKG2D-ligand expression. The absence of NKG2D signaling in NK cells significantly improves NPC-derived neuron survival and differentiation. These data illustrate the importance of innate immune mechanisms in graft outcome and the potential value of identifying and targeting NK cell-activating ligands that may be expressed by stem cell derived grafts. STEM Cells 2013;31:2024-2030

Ancillary