PD-1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator-activated receptor-γ

Immun Inflamm Dis. 2020 Mar;8(1):8-23. doi: 10.1002/iid3.279. Epub 2019 Nov 19.


Introduction: Innate lymphoid cells (ILCs) can provide early cytokine help against a variety of pathogens in the lungs and gastrointestinal tract. Type 2 ILC (ILC2) are comparable to T helper 2 cells found in the adaptive immune system, which secrete cytokines such as interleukin 5 (IL-5) and IL-13 and have been found to play roles in host defense against helminth infections and in allergic responses. Recent studies have identified that programmed cell death protein 1 (PD-1) and peroxisome proliferator activated receptor-γ (PPAR-γ) are highly expressed by ILC2. We examined whether PD-1 plays a role in ILC2 function and whether there was any connection between PD-1 and PPAR-γ METHODS: To ensure that only innate immune cells were present, ILC2 cells were examined from RAG1-/- and PD-1-/- xRAG1-/- mice under steady-state or following inoculation with IL-33. We also tested ILC2 generated from bone marrow of RAG1-/- and PD-1-/- xRAG1-/- mice for their production of cytokines. These in vitro-derived ILC2 were also exposed to agonist and antagonist of PPAR-γ.

Results: We found that ILC2 from PD-1-/- xRAG1-/- mice had reduced frequencies of IL-5 and IL-13 producing cells both in vitro upon IL-33 stimulation and in vivo following intraperitoneal administration of IL-33 when compared with ILC2 from RAG1-/- mice. However, by adding IL-2, IL-25, and thymic stromal lymphopoietin to the in vitro cultures, the frequency of IL-5 and IL-13 expressing ILC2 from PD-1-/- xRAG1-/- mice became similar to the frequency observed for ILC2 from RAG1-/- mice. In addition, PPAR-γ agonists and antagonists were found to increase and decrease PD-1 expression on ILC2 respectively.

Conclusions: These findings illustrate that chronic loss of PD-1 plays a role in ILC2 function and PD-1 expression can be modulated by PPAR-γ.

Keywords: ILC2; cytokine; peroxisome proliferator-activated receptor-γ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism*
  • Homeodomain Proteins / genetics
  • Hypersensitivity / immunology
  • Immunity, Innate*
  • Lymphocytes / cytology*
  • Lymphocytes / metabolism
  • Lymphoid Progenitor Cells / cytology*
  • Lymphoid Progenitor Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR gamma / agonists
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / metabolism*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • Th2 Cells / immunology


  • Cytokines
  • Homeodomain Proteins
  • PPAR gamma
  • Pdcd1 protein, mouse
  • Pparg protein, mouse
  • Programmed Cell Death 1 Receptor
  • RAG-1 protein