Engineering of Immune Checkpoints B7-H3 and CD155 Enhances Immune Compatibility of MHC-I IPSCs for β Cell Replacement

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Sep 28

PMID 36170817

Authors

Raniero Chimienti

Tania Baccega

Silvia Torchio

Fabio Manenti

Silvia Pellegrini

Alessandro Cospito

Angelo Amabile

Marta Tiffany Lombardo

Paolo Monti

Valeria Sordi

Angelo Lombardo

Mauro Malnati

Lorenzo Piemonti

Affiliations

Soon will be listed here.

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 CD16 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.

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