Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells.
The costimulatory molecule 4-1BB and its ligand 4-1BBL can control adaptive immunity, but here we show that their interaction also suppressed myelopoiesis. We found that 4-1BBL was expressed on hematopoietic stem cells, differentiating common myeloid progenitors and granulocyte-macrophage progenitors, and 4-1BB was inducible on activated myeloid progenitors. Steady-state numbers of granulocyte-macrophage progenitors, myeloid-lineage cells and mature dendritic cells were higher in 4-1BB- and 4-1BBL-deficient mice, indicative of a negative function, and we confirmed that result with bone marrow chimeras and in vitro, where the absence of interactions between 4-1BB and 4-1BBL led to enhanced differentiation into dendritic cell lineages. The regulatory activity was mediated by 4-1BBL, with binding by 4-1BB inhibiting differentiation of myeloid progenitors. Thus, 4-1BB and 4-1BBL have a previously unknown function in limiting myelopoiesis and the development of dendritic cells.
Lee
Seung-Woo
SW
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Park
Yunji
Y
So
Takanori
T
Kwon
Byoung S
BS
Cheroutre
Hilde
H
Mittler
Robert S
RS
Croft
Michael
M
D053330:4-1BB Ligand / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D051379:Mice; D038042:Myelopoiesis; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D053330:4-1BB Ligand; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha