@article{f9bc21196a5749d286ad5d7d2dc6361a,
title = "Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice",
abstract = "Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against β-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.",
keywords = "Autoimmune diabetes, Exhausted CD8 T cells, Monocytederived macrophages, PD-1 blockade",
author = "Hao Hu and Zakharov, {Pavel N.} and Peterson, {Orion J.} and Unanue, {Emil R.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Katherine Frederick for the maintenance of the mouse colony; all members of the E.R.U. laboratory for providing advice and critical thoughts on many aspects of this project; the Genome Technology Access Center core facility at the Washington University in St. Louis (https://gtac.wustl.edu/) for single-cell RNA-sequencing library preparation and sequencing; and the Center for High Performance Computing at Washington University in St. Louis for providing access to high-performance computing resources, including Malcolm Tobias for technical assistance. This study received support from NIH Grants DK 058177 and AI114551, and from the Juvenile Diabetes Research Foundation. The laboratory receives general support from the Kilo Diabetes and Vascular Research Foundation. Funding Information: We thank Katherine Frederick for the maintenance of the mouse colony; all members of the E.R.U. laboratory for providing advice and critical thoughts on many aspects of this project; the Genome Technology Access Center core facility at the Washington University in St. Louis (https://gtac.wustl.edu/) for single-cell RNA-sequencing library preparation and sequencing; and the Center for High Performance Computing at Washington University in St. Louis for providing access to high-performance computing resources, including Malcolm Tobias for technical assistance. This study received support from NIH Grants DK 058177 and AI114551, and from the Juvenile Diabetes Research Foundation. The laboratory receives general support from the Kilo Diabetes and Vascular Research Foundation. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = dec,
day = "8",
doi = "10.1073/pnas.2019743117",
language = "English",
volume = "117",
pages = "31319--31330",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "49",
}