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Identification of regulatory functions for 4-1BB and 4-1BBL in myelopoiesis and the development of dendritic cells

2008; Nature Portfolio; Volume: 9; Issue: 8 Linguagem: Inglês

10.1038/ni.1632

1529-2916

Seung-Woo Lee, Yunji Park, Takanori So, Byoung S. Kwon, Hilde Cheroutre, Robert S. Mittler, Michael Croft,

Immunotherapy and Immune Responses

The TNF receptor 4-1BB functions as a costimulatory molecule in T cells. Croft and colleagues show that binding of 4-1BB to its ligand regulates the production of dendritic cells by inhibiting myelopoiesis. 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.