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 / Chimienti, Raniero; Baccega, Tania; Torchio, Silvia; Manenti, Fabio; Pellegrini, Silvia; Cospito, Alessandro; Amabile, Angelo; Lombardo, Marta Tiffany; Monti, Paolo; Sordi, Valeria; Lombardo, Angelo; Malnati, Mauro; Piemonti, Lorenzo. - In: CELL REPORTS. - ISSN 2211-1247. - 40:13(2022), p. 111423. [10.1016/j.celrep.2022.111423]
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
