Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice

Hao Hu, Pavel N. Zakharov, Orion J. Peterson, Emil R. Unanue

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)31319-31330
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number49
DOIs
StatePublished - Dec 8 2020

Keywords

  • Autoimmune diabetes
  • Exhausted CD8 T cells
  • Monocytederived macrophages
  • PD-1 blockade

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