Absence of Major Histocompatibility Complex Class I on Neural Stem Cells Does Not Permit Natural Killer Cell Killing and Prevents Recognition by Alloreactive Cytotoxic T Lymphocytes In Vitro

Abstract

Potential applications of neural stem cells (NSCs) for transplantation requires understanding myosin heavy chain (MHC) expression and the ability of T cells and natural killer (NK) cells to recognize this progenitor population. Cells from the cortices of day-13 embryonic (E13) B6 (H-2b) mice were explanted and cultured to expand NSCs. Analysis of P2-P17-cultured cells using anti-MHC class I/II monoclonal antibodies (mAbs) showed marginal expression of both products. Although recombinant murine interferon-gamma (rmIFNγ) exposure did not alter the multipotential capacity of these stem cells, titration of mrIFNγ NSC cultures demonstrated that MHC molecules could be strongly upregulated after addition of 3 ng/ml rmIFNγ for 60 hours. To assess the susceptibility of NSCs with low or absent versus high levels of MHC expression to lysis by cytotoxic T lymphocyte (CTL) and NK populations, untreated and rmIFNγ-treated NSC target cells were examined. Untreated NSCs were not recognized by BALB/c (H-2d) allospecific anti-H-2 b CTL, consistent with the mAb findings; however, upregulation of MHC products on both early and later passaged NSCs resulted in their efficient lysis by CTL. NK cells were prepared from syngeneic B6 or allogeneic BALB/c mice. Although NK cells effectively killed control YAC-1 target cells, these effectors did not kill MHC-deficient (or expressing) NSC targets. Thus, similar to hematopoietic, embryonic, and mesenchymal stem cell populations, unmanipulated NSCs are not readily killed by T and NK cells. These findings suggest that following transplant into syngeneic or allogeneic recipients, NSCs may exhibit diminished susceptibility to clearance by host T- and NK-cell populations.