TY - JOUR
T1 - Human ectoenzyme-expressing ILC3: Immunosuppressive innate cells that are depleted in graft-versus-host disease
AU - Hazenberg, Mette D.
AU - Haverkate, Nienke J. E.
AU - van Lier, Yannouck F.
AU - Spits, Hergen
AU - Krabbendam, Lisette
AU - Bemelman, Willem A.
AU - Buskens, Christianne J.
AU - Blom, Bianca
AU - Shikhagaie, Medya M.
PY - 2019
Y1 - 2019
N2 - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often associated with chemotherapy- and radiotherapy-induced host tissue damage, leading to graft-versus-host disease (GVHD). Innate lymphoid cells (ILC) have an essential role in tissue homeostasis and tissue repair via their production of interleukin (IL)-22, which acts on intestinal stem cells. The tissue healing capacities of ILC via IL-22 in the context of allo-HSCT and GVHD has previously been demonstrated in a mouse model for acute GVHD. We investigated potential other ways of ILC-mediated tissue protection against GVHD. Tissue injury leads to the release of danger-associated molecular patterns (DAMPs). DAMPs interact with purinergic receptors and ectoenzymes on immune cells and induce pleiotropic effects, including activation of proinflammatory antigen-presenting cells and immunosuppressive effects via the generation of adenosine. Here, we report a novel subset of human ILC3 that coexpress the ectoenzymes CD39 and CD73 (ecto+ ILC3). Ecto+ ILC3 express RORgt and were present in the oral-gastrointestinal tract and bone marrow. ILC3 ectoenzyme expression is modulated by the proinflammatory cytokine IL-1b. Extracellular adenosine triphosphate (eATP) stimulated ecto+ ILC3 to produce IL-22 and adenosine. Activated ecto+ ILC3 suppressed autologous T-cell proliferation in coculture experiments via the production of adenosine. In allo-HSCT recipients, intestinal GVHD was associated with reduced proportions of ecto+ ILC3 and decreased levels of adenosine and its metabolite inosine. Taken together, ecto+ ILC3 have immunosuppressive properties, but in patients with GVHD, ecto+ ILC3 are depleted. A lack of ecto+ ILC3 and subsequent reduced capacity to neutralize DAMPs may contribute to the development of GVHD.
AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often associated with chemotherapy- and radiotherapy-induced host tissue damage, leading to graft-versus-host disease (GVHD). Innate lymphoid cells (ILC) have an essential role in tissue homeostasis and tissue repair via their production of interleukin (IL)-22, which acts on intestinal stem cells. The tissue healing capacities of ILC via IL-22 in the context of allo-HSCT and GVHD has previously been demonstrated in a mouse model for acute GVHD. We investigated potential other ways of ILC-mediated tissue protection against GVHD. Tissue injury leads to the release of danger-associated molecular patterns (DAMPs). DAMPs interact with purinergic receptors and ectoenzymes on immune cells and induce pleiotropic effects, including activation of proinflammatory antigen-presenting cells and immunosuppressive effects via the generation of adenosine. Here, we report a novel subset of human ILC3 that coexpress the ectoenzymes CD39 and CD73 (ecto+ ILC3). Ecto+ ILC3 express RORgt and were present in the oral-gastrointestinal tract and bone marrow. ILC3 ectoenzyme expression is modulated by the proinflammatory cytokine IL-1b. Extracellular adenosine triphosphate (eATP) stimulated ecto+ ILC3 to produce IL-22 and adenosine. Activated ecto+ ILC3 suppressed autologous T-cell proliferation in coculture experiments via the production of adenosine. In allo-HSCT recipients, intestinal GVHD was associated with reduced proportions of ecto+ ILC3 and decreased levels of adenosine and its metabolite inosine. Taken together, ecto+ ILC3 have immunosuppressive properties, but in patients with GVHD, ecto+ ILC3 are depleted. A lack of ecto+ ILC3 and subsequent reduced capacity to neutralize DAMPs may contribute to the development of GVHD.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85076381632&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31751473
U2 - https://doi.org/10.1182/bloodadvances.2019000176
DO - https://doi.org/10.1182/bloodadvances.2019000176
M3 - Article
C2 - 31751473
SN - 2473-9529
VL - 3
SP - 3650
EP - 3660
JO - Blood advances
JF - Blood advances
IS - 22
ER -