Induced pluripotent stem cells (iPSCs) represent a source from which β cells can be derived for diabetes replacement therapy. However, their application may be hindered by immune-mediated responses. Although abrogation of major histocompatibility complex class I (MHC-I) can address this issue, it may trigger natural killer (NK) cells through missing-self recognition mechanisms. By profiling the relevant NK-activating ligands on iPSCs during in vitro differentiation into pancreatic β cells, we find that they express high levels of B7-H3 and CD155. Hypothesizing that such surface ligands could be involved in the amplification of NK-activating signals following missing-self, we generate MHC-I-deprived B7-H3-/-, CD155-/-, and B7-H3-/-/CD155-/- iPSCs. All engineered lines correctly differentiate into insulin-secreting β cells and are protected from cell lysis mediated by CD16dim and CD16+ NK subpopulations both in vitro and in vivo in NSG mice. Our data support targeted disruption of NK-activating ligands to enhance the transplant compatibility of MHC-I-/- iPSC pancreatic derivatives.

Engineering of immune checkpoints B7-H3 and CD155 enhances immune compatibility of MHC-I-/- iPSCs for β cell replacement

Baccega, Tania;Torchio, Silvia;Lombardo, Angelo;Piemonti, Lorenzo
2022-01-01

Abstract

Induced pluripotent stem cells (iPSCs) represent a source from which β cells can be derived for diabetes replacement therapy. However, their application may be hindered by immune-mediated responses. Although abrogation of major histocompatibility complex class I (MHC-I) can address this issue, it may trigger natural killer (NK) cells through missing-self recognition mechanisms. By profiling the relevant NK-activating ligands on iPSCs during in vitro differentiation into pancreatic β cells, we find that they express high levels of B7-H3 and CD155. Hypothesizing that such surface ligands could be involved in the amplification of NK-activating signals following missing-self, we generate MHC-I-deprived B7-H3-/-, CD155-/-, and B7-H3-/-/CD155-/- iPSCs. All engineered lines correctly differentiate into insulin-secreting β cells and are protected from cell lysis mediated by CD16dim and CD16+ NK subpopulations both in vitro and in vivo in NSG mice. Our data support targeted disruption of NK-activating ligands to enhance the transplant compatibility of MHC-I-/- iPSC pancreatic derivatives.
CP: Immunology
CP: Stem cell research
MHC class I
NK activation ligands
NK cells
cell engineering
controlled immune evasion
differentiation
iPS cells
immune checkpoints
type 1 diabetes
β cells
Animals
Histocompatibility Antigens Class I
Ligands
Mice
Induced Pluripotent Stem Cells
Insulin-Secreting Cells
Insulins
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/132591
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